Modulators of cftr

ABSTRACT

Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating CFTR mediated diseases using compounds of the present invention.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. §119 to U.S.provisional patent application Ser. No. 60/928,334, filed May 9, 2007,the entire contents of which are incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to modulators of Cystic FibrosisTransmembrane Conductance Regulator (“CFTR”), compositions thereof, andmethods therewith. The present invention also relates to methods oftreating CFTR mediated diseases using such modulators.

BACKGROUND OF THE INVENTION

ABC transporters are a family of membrane transporter proteins thatregulate the transport of a wide variety of pharmacological agents,potentially toxic drugs, and xenobiotics, as well as anions. ABCtransporters are homologous membrane proteins that bind and use cellularadenosine triphosphate (ATP) for their specific activities. Some ofthese transporters were discovered as multi-drug resistance proteins(like the MDR1-P glycoprotein, or the multi-drug resistance protein,MRP1), defending malignant cancer cells against chemotherapeutic agents.To date, 48 ABC Transporters have been identified and grouped into 7families based on their sequence identity and function.

ABC transporters regulate a variety of important physiological roleswithin the body and provide defense against harmful environmentalcompounds. Because of this, they represent important potential drugtargets for the treatment of diseases associated with defects in thetransporter, prevention of drug transport out of the target cell, andintervention in other diseases in which modulation of ABC transporteractivity may be beneficial.

One member of the ABC transporter family commonly associated withdisease is the cAMP/ATP-mediated anion channel, CFTR. CFTR is expressedin a variety of cells types, including absorptive and secretoryepithelia cells, where it regulates anion flux across the membrane, aswell as the activity of other ion channels and proteins. In epitheliacells, normal functioning of CFTR is critical for the maintenance ofelectrolyte transport throughout the body, including respiratory anddigestive tissue. CFTR is composed of approximately 1480 amino acidsthat encode a protein made up of a tandem repeat of transmembranedomains, each containing six transmembrane helices and a nucleotidebinding domain. The two transmembrane domains are linked by a large,polar, regulatory (R)-domain with multiple phosphorylation sites thatregulate channel activity and cellular trafficking.

The gene encoding CFTR has been identified and sequenced (See Gregory,R. J. et al. (1990) Nature 347:382-386; Rich, D. P. et al. (1990) Nature347:358-362), (Riordan, J. R. et al. (1989) Science 245:1066-1073). Adefect in this gene causes mutations in CFTR resulting in CysticFibrosis (“CF”), the most common fatal genetic disease in humans. CysticFibrosis affects approximately one in every 2,500 infants in the UnitedStates. Within the general United States population, up to 10 millionpeople carry a single copy of the defective gene without apparent illeffects. In contrast, individuals with two copies of the CF associatedgene suffer from the debilitating and fatal effects of CF, includingchronic lung disease.

In patients with cystic fibrosis, mutations in CFTR endogenouslyexpressed in respiratory epithelia leads to reduced apical anionsecretion causing an imbalance in ion and fluid transport. The resultingdecrease in anion transport contributes to enhanced mucus accumulationin the lung and the accompanying microbial infections that ultimatelycause death in CF patients. In addition to respiratory disease, CFpatients typically suffer from gastrointestinal problems and pancreaticinsufficiency that, if left untreated, results in death. In addition,the majority of males with cystic fibrosis are infertile and fertilityis decreased among females with cystic fibrosis. In contrast to thesevere effects of two copies of the CF associated gene, individuals witha single copy of the CF associated gene exhibit increased resistance tocholera and to dehydration resulting from diarrhea—perhaps explainingthe relatively high frequency of the CF gene within the population.

Sequence analysis of the CFTR gene of CF chromosomes has revealed avariety of disease causing mutations (Cutting, G. R. et al. (1990)Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863:870; and Kerem,B-S. et al. (1989) Science 245:1073-1080; Kerem, B-S et al. (1990) Proc.Natl. Acad. Sci. USA 87:8447-8451). To date, >1000 disease causingmutations in the CF gene have been identified(http://www.genet.sickkids.on.ca/cftr/). The most prevalent mutation isa deletion of phenylalanine at position 508 of the CFTR amino acidsequence, and is commonly referred to as ΔF508-CFTR. This mutationoccurs in approximately 70% of the cases of cystic fibrosis and isassociated with a severe disease.

The deletion of residue 508 in ΔF508-CFTR prevents the nascent proteinfrom folding correctly. This results in the inability of the mutantprotein to exit the ER, and traffic to the plasma membrane. As a result,the number of channels present in the membrane is far less than observedin cells expressing wild-type CFTR. In addition to impaired trafficking,the mutation results in defective channel gating. Together, the reducednumber of channels in the membrane and the defective gating lead toreduced anion transport across epithelia leading to defective ion andfluid transport. (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). Studieshave shown, however, that the reduced numbers of ΔF508-CFTR in themembrane are functional, albeit less than wild-type CFTR. (Dalemans etal. (1991), Nature Lond. 354: 526-528; Denning et al., supra; Pasyk andFoskett (1995), J. Cell. Biochem. 270: 12347-50). In addition toΔF508-CFTR, other disease causing mutations in CFTR that result indefective trafficking, synthesis, and/or channel gating could be up- ordown-regulated to alter anion secretion and modify disease progressionand/or severity.

Although CFTR transports a variety of molecules in addition to anions,it is clear that this role (the transport of anions) represents oneelement in an important mechanism of transporting ions and water acrossthe epithelium. The other elements include the epithelial Na⁺ channel,ENaC, Na⁺/2Cl⁻/K⁺ co-transporter, Na⁺-K⁺-ATPase pump and the basolateralmembrane K⁺ channels, that are responsible for the uptake of chlorideinto the cell.

These elements work together to achieve directional transport across theepithelium via their selective expression and localization within thecell. Chloride absorption takes place by the coordinated activity ofENaC and CFTR present on the apical membrane and the Na⁺-K⁺-ATPase pumpand Cl— channels expressed on the basolateral surface of the cell.Secondary active transport of chloride from the luminal side leads tothe accumulation of intracellular chloride, which can then passivelyleave the cell via Cl⁻ channels, resulting in a vectorial transport.Arrangement of Na⁺/2Cl⁻/K⁺co-transporter, Na⁺—K⁺-ATPase pump and thebasolateral membrane K⁺ channels on the basolateral surface and CFTR onthe luminal side coordinate the secretion of chloride via CFTR on theluminal side. Because water is probably never actively transporteditself, its flow across epithelia depends on tiny transepithelialosmotic gradients generated by the bulk flow of sodium and chloride.

In addition to Cystic Fibrosis, modulation of CFTR activity may bebeneficial for other diseases not directly caused by mutations in CFTR,such as secretory diseases and other protein folding diseases mediatedby CFTR. These include, but are not limited to, chronic obstructivepulmonary disease (COPD), dry eye disease, and Sjögren's Syndrome.

COPD is characterized by airflow limitation that is progressive and notfully reversible. The airflow limitation is due to mucus hypersecretion,emphysema, and bronchiolitis. Activators of mutant or wild-type CFTRoffer a potential treatment of mucus hypersecretion and impairedmucociliary clearance that is common in COPD. Specifically, increasinganion secretion across CFTR may facilitate fluid transport into theairway surface liquid to hydrate the mucus and optimized periciliaryfluid viscosity. This would lead to enhanced mucociliary clearance and areduction in the symptoms associated with COPD. Dry eye disease ischaracterized by a decrease in tear aqueous production and abnormal tearfilm lipid, protein and mucin profiles. There are many causes of dryeye, some of which include age, Lasik eye surgery, arthritis,medications, chemical/thermal burns, allergies, and diseases, such asCystic Fibrosis and Sjögrens's syndrome. Increasing anion secretion viaCFTR would enhance fluid transport from the corneal endothelial cellsand secretory glands surrounding the eye to increase corneal hydration.This would help to alleviate the symptoms associated with dry eyedisease. Sjögrens's syndrome is an autoimmune disease in which theimmune system attacks moisture-producing glands throughout the body,including the eye, mouth, skin, respiratory tissue, liver, vagina, andgut. Symptoms, include, dry eye, mouth, and vagina, as well as lungdisease. The disease is also associated with rheumatoid arthritis,systemic lupus, systemic sclerosis, and polymypositis/dermatomyositis.Defective protein trafficking is believed to cause the disease, forwhich treatment options are limited. Modulators of CFTR activity mayhydrate the various organs afflicted by the disease and help to elevatethe associated symptoms.

As discussed above, it is believed that the deletion of residue 508 inΔF508-CFTR prevents the nascent protein from folding correctly,resulting in the inability of this mutant protein to exit the ER, andtraffic to the plasma membrane. As a result, insufficient amounts of themature protein are present at the plasma membrane and chloride transportwithin epithelial tissues is significantly reduced. In fact, thiscellular phenomenon of defective ER processing of ABC transporters bythe ER machinery has been shown to be the underlying basis not only forCF disease, but for a wide range of other isolated and inheriteddiseases. The two ways that the ER machinery can malfunction is eitherby loss of coupling to ER export of the proteins leading to degradation,or by the ER accumulation of these defective/misfolded proteins [AridorM, et al., Nature Med., 5(7), pp 745-751 (1999); Shastry, B. S., et al.,Neurochem. International, 43, pp 1-7 (2003); Rutishauser, J., et al.,Swiss Med Wkly, 132, pp 211-222 (2002); Morello, J P et al., TIPS, 21,pp. 466-469 (2000); Bross P., et al., Human Mut., 14, pp. 186-198(1999)]. The diseases associated with the first class of ER malfunctionare Cystic fibrosis (due to misfolded ΔF508-CFTR as discussed above),Hereditary emphysema (due to al-antitrypsin; non Piz variants),Hereditary hemochromatosis, Coagulation-Fibrinolysis deficiencies, suchas Protein C deficiency, Type 1 hereditary angioedema, Lipid processingdeficiencies, such as Familial hypercholesterolemia, Type 1chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, suchas I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses (due to Lysosomalprocessing enzymes), Sandhof/Tay-Sachs (due to (3-Hexosaminidase),Crigler-Najjar type II (due to UDP-glucuronyl-sialyc-transferase),Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus (due to Insulinreceptor), Laron dwarfism (due to Growth hormone receptor),Myleoperoxidase deficiency, Primary hypoparathyroidism (due toPreproparathyroid hormone), Melanoma (due to Tyrosinase). The diseasesassociated with the latter class of ER malfunction are Glycanosis CDGtype 1, Hereditary emphysema (due to al-Antitrypsin (PiZ variant),Congenital hyperthyroidism, Osteogenesis imperfecta (due to Type I, II,IV procollagen), Hereditary hypofibrinogenemia (due to Fibrinogen), ACTdeficiency (due to al-Antichymotrypsin), Diabetes insipidus (DI),Neurophyseal DI (due to Vasopvessin hormone/V2-receptor), Neprogenic DI(due to Aquaporin II), Charcot-Marie Tooth syndrome (due to Peripheralmyelin protein 22), Perlizaeus-Merzbacher disease, neurodegenerativediseases such as Alzheimer's disease (due to PAPP and presenilins),Parkinson's disease, Amyotrophic lateral sclerosis, Progressivesupranuclear plasy, Pick's disease, several polyglutamine neurologicaldisorders asuch as Huntington, Spinocerebullar ataxia type I, Spinal andbulbar muscular atrophy, Dentatorubal pallidoluysian, and Myotonicdystrophy, as well as Spongiform encephalopathies, such as HereditaryCreutzfeldt-Jakob disease (due to Prion protein processing defect),Fabry disease (due to lysosomal α-galactosidase A) andStraussler-Scheinker syndrome (due to Prp processing defect).

In addition to up-regulation of CFTR activity, reducing anion secretionby CFTR modulators may be beneficial for the treatment of secretorydiarrheas, in which epithelial water transport is dramatically increasedas a result of secretagogue activated chloride transport. The mechanisminvolves elevation of cAMP and stimulation of CFTR.

Although there are numerous causes of diarrhea, the major consequencesof diarrheal diseases, resulting from excessive chloride transport arecommon to all, and include dehydration, acidosis, impaired growth anddeath.

Acute and chronic diarrheas represent a major medical problem in manyareas of the world. Diarrhea is both a significant factor inmalnutrition and the leading cause of death (5,000,000 deaths/year) inchildren less than five years old.

Secretory diarrheas are also a dangerous condition in patients ofacquired immunodeficiency syndrome (AIDS) and chronic inflammatory boweldisease (IBD). 16 million travelers to developing countries fromindustrialized nations every year develop diarrhea, with the severityand number of cases of diarrhea varying depending on the country andarea of travel.

Diarrhea in barn animals and pets such as cows, pigs, and horses, sheep,goats, cats and dogs, also known as scours, is a major cause of death inthese animals. Diarrhea can result from any major transition, such asweaning or physical movement, as well as in response to a variety ofbacterial or viral infections and generally occurs within the first fewhours of the animal's life.

The most common diarrhea causing bacteria is enterotoxogenic E-coli(ETEC) having the K99 pilus antigen. Common viral causes of diarrheainclude rotavirus and coronavirus. Other infectious agents includecryptosporidium, giardia lamblia, and salmonella, among others.

Symptoms of rotaviral infection include excretion of watery feces,dehydration and weakness. Coronavirus causes a more severe illness inthe newborn animals, and has a higher mortality rate than rotaviralinfection. Often, however, a young animal may be infected with more thanone virus or with a combination of viral and bacterial microorganisms atone time. This dramatically increases the severity of the disease.

There is a need for modulators of CFTR activity that can be used tomodulate the activity of CFTR in the cell membrane of a mammal.

There is a need for methods of treating CFTR-mediated diseases usingsuch modulators of CFTR activity.

There is a need for methods of modulating CFTR activity in an ex vivocell membrane of a mammal

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are useful asmodulators of CFTR. These compounds have the general formula (I):

or a pharmaceutically acceptable salt thereof, wherein R₁, R′₁, R₂, R₃,R′₃, R₄, and n are described herein.

These compounds and pharmaceutically acceptable compositions are usefulfor treating or lessening the severity of a variety of diseases,disorders, or conditions, including, but not limited to, cysticfibrosis, hereditary emphysema, hereditary hemochromatosis,coagulation-fibrinolysis deficiencies, such as protein C deficiency,Type 1 hereditary angioedema, lipid processing deficiencies, such asfamilial hypercholesterolemia, Type 1 chylomicronemia,abetalipoproteinemia, lysosomal storage diseases, such as I-celldisease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs,Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, DiabetesMellitus, Laron dwarfism, myleoperoxidase deficiency, primaryhypoparathyroidism, melanoma, glycanosis CDG type 1, hereditaryemphysema, congenital hyperthyroidism, osteogenesis imperfecta,hereditary hypofibrinogenemia, ACT deficiency, Diabetes Insipidus (DI),neurophyseal DI, neprogenic DI, Charcot-Marie Tooth syndrome,Perlizaeus-Merzbacher disease, neurodegenerative diseases such asAlzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis,progressive supranuclear plasy, Pick's disease, several polyglutamineneurological disorders asuch as Huntington, spinocerebullar ataxia typeI, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, andmyotonic dystrophy, as well as spongiform encephalopathies, such ashereditary Creutzfeldt-Jakob disease, Fabry disease,Straussler-Scheinker syndrome, COPD, dry-eye disease, and Sjögren'sdisease.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein, the following definitions shall apply unless otherwiseindicated.

The term “ABC-transporter” as used herein means an ABC-transporterprotein or a fragment thereof comprising at least one binding domain,wherein said protein or fragment thereof is present in vivo or in vitro.The term “binding domain” as used herein means a domain on theABC-transporter that can bind to a modulator. See, e.g., Hwang, T. C. etal., J. Gen. Physiol. (1998): 111(3), 477-90.

The term “CFTR” as used herein means cystic fibrosis transmembraneconductance regulator or a mutation thereof capable of regulatoractivity, including, but not limited to, ΔF508 CFTR and G551D CFTR (see,e.g., http://www.genet.sickkids.on.ca/cftr/, for CFTR mutations).

The term “modulating” as used herein means increasing or decreasing,e.g. activity, by a measurable amount. Compounds that modulate ABCTransporter activity, such as CFTR activity, by increasing the activityof the ABC Transporter, e.g., a CFTR anion channel, are called agonists.Compounds that modulate ABC Transporter activity, such as CFTR activity,by decreasing the activity of the ABC Transporter, e.g., CFTR anionchannel, are called antagonists. An agonist interacts with an ABCTransporter, such as CFTR anion channel, to increase the ability of thereceptor to transduce an intracellular signal in response to endogenousligand binding. An antagonist interacts with an ABC Transporter, such asCFTR, and competes with the endogenous ligand(s) or substrate(s) forbinding site(s) on the receptor to decrease the ability of the receptorto transduce an intracellular signal in response to endogenous ligandbinding.

The phrase “treating or reducing the severity of an ABC Transportermediated disease” refers both to treatments for diseases that aredirectly caused by ABC Transporter and/or CFTR activities andalleviation of symptoms of diseases not directly caused by ABCTransporter and/or CFTR anion channel activities. Examples of diseaseswhose symptoms may be affected by ABC Transporter and/or CFTR activityinclude, but are not limited to, Cystic fibrosis, Hereditary emphysema,Hereditary hemochromatosis, Coagulation-Fibrinolysis deficiencies, suchas Protein C deficiency, Type 1 hereditary angioedema, Lipid processingdeficiencies, such as Familial hypercholesterolemia, Type 1chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, suchas I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses,Sandhof/Tay-Sachs, Crigler-Najjar type II,Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus, Laron dwarfism,Myleoperoxidase deficiency, Primary hypoparathyroidism, Melanoma,Glycanosis CDG type 1, Hereditary emphysema, Congenital hyperthyroidism,Osteogenesis imperfecta, Hereditary hypofibrinogenemia, ACT deficiency,Diabetes insipidus (DI), Neurophyseal DI, Neprogenic DI, Charcot-MarieTooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerativediseases such as Alzheimer's disease, Parkinson's disease, Amyotrophiclateral sclerosis, Progressive supranuclear plasy, Pick's disease,several polyglutamine neurological disorders asuch as Huntington,Spinocerebullar ataxia type I, Spinal and bulbar muscular atrophy,Dentatorubal pallidoluysian, and Myotonic dystrophy, as well asSpongiform encephalopathies, such as Hereditary Creutzfeldt-Jakobdisease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eyedisease, and Sjogren's disease.

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75th Ed. Additionally, generalprinciples of organic chemistry are described in “Organic Chemistry”,Thomas Sorrell, University Science Books, Sausolito: 1999, and “March'sAdvanced Organic Chemistry”, 5th Ed., Ed.: Smith, M. B. and March, J.,John Wiley & Sons, New York: 2001, the entire contents of which arehereby incorporated by reference.

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed. Additionally, generalprinciples of organic chemistry are described in “Organic Chemistry”,Thomas Sorrell, University Science Books, Sausalito: 1999, and “March'sAdvanced Organic Chemistry”, 5th Ed., Ed.: Smith, M. B. and March, J.,John Wiley & Sons, New York: 2001.

As used herein the term “aliphatic” encompasses the terms alkyl,alkenyl, alkynyl, each of which being optionally substituted as setforth below.

As used herein, an “alkyl” group refers to a saturated aliphatichydrocarbon group containing 1-8 (e.g., 1-6 or 1-4) carbon atoms. Analkyl group can be straight or branched. Examples of alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or2-ethylhexyl. An alkyl group can be substituted (i.e., optionallysubstituted) with one or more substituents such as halo, cycloaliphatic[e.g., cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g.,heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy,aroyl, heteroaroyl, acyl [e.g., (aliphatic)carbonyl,(cycloaliphatic)carbonyl, or (heterocycloaliphatic)carbonyl], nitro,cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino,aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,(heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino,heteroaralkylcarbonylamino], amino [e.g., aliphaticamino,cycloaliphaticamino, or heterocycloaliphaticamino], sulfonyl [e.g.,aliphaticsulfonyl], sulfinyl, sulfanyl, sulfoxy, urea, thiourea,sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy,heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy,heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy. Withoutlimitation, some examples of substituted alkyls include carboxyalkyl(such as HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl),cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, hydroxyalkyl, aralkyl,(alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as(alkylsulfonylamino)alkyl), aminoalkyl, amidoalkyl,(cycloaliphatic)alkyl, cyanoalkyl, or haloalkyl.

As used herein, an “alkenyl” group refers to an aliphatic carbon groupthat contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and at least onedouble bond. Like an alkyl group, an alkenyl group can be straight orbranched. Examples of an alkenyl group include, but are not limited to,allyl, isoprenyl, 2-butenyl, and 2-hexenyl. An alkenyl group can beoptionally substituted with one or more substituents such as halo,cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, alkoxy, aroyl,heteroaroyl, acyl [e.g., (cycloaliphatic)carbonyl, or(heterocycloaliphatic)carbonyl], nitro, cyano, acyl [e.g.,aliphaticcarbonyl, cycloaliphaticcarbonyl, arylcarbonyl,heterocycloaliphaticcarbonyl or heteroarylcarbonyl], amido [e.g.,(cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino,(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,heteroarylcarbonylamino, heteroaralkylcarbonylamino alkylaminocarbonyl,cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl,arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g.,aliphaticamino, or aliphaticsulfonylamino], sulfonyl [e.g.,alkylsulfonyl, cycloaliphaticsulfonyl, or arylsulfonyl], sulfinyl,sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, carboxy,carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy,heteroaryloxy, aralkyloxy, heteroarylalkoxy, alkoxycarbonyl,alkylcarbonyloxy, or hydroxy.

As used herein, an “alkynyl” group refers to an aliphatic carbon groupthat contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and has at least onetriple bond. An alkynyl group can be straight or branched. Examples ofan alkynyl group include, but are not limited to, propargyl and butynyl.An alkynyl group can be optionally substituted with one or moresubstituents such as aroyl, heteroaroyl, alkoxy, cycloalkyloxy,heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxy,cyano, halo, hydroxy, sulfo, mercapto, sulfanyl [e.g., aliphaticsulfanylor cycloaliphaticsulfanyl], sulfinyl [e.g., aliphaticsulfinyl orcycloaliphaticsulfinyl], sulfonyl [e.g., aliphaticsulfonyl,aliphaticaminosulfonyl, or cycloaliphaticsulfonyl], amido [e g,aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino,cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl,cycloalkylcarbonylamino, arylaminocarbonyl, arylcarbonylamino,aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,(cycloalkylalkyl)carbonylamino, heteroaralkylcarbonylamino,heteroarylcarbonylamino or heteroarylaminocarbonyl], urea, thiourea,sulfamoyl, sulfamide, alkoxycarbonyl, alkylcarbonyloxy, cycloaliphatic,heterocycloaliphatic, aryl, heteroaryl, acyl [e.g.,(cycloaliphatic)carbonyl or (heterocycloaliphatic)carbonyl], amino[e.g., aliphaticamino], sulfoxy, oxo, carboxy, carbamoyl,(cycloaliphatic)oxy, (heterocycloaliphatic)oxy, or (heteroaryl)alkoxy.

As used herein, an “amido” encompasses both “aminocarbonyl” and“carbonylamino” These terms when used alone or in connection withanother group refers to an amido group such as N(R^(X)R^(Y))—C(O)— orR^(Y)C(O)—N(R^(X))— when used terminally and —C(O)—N(R^(X))— or—N(R^(X))—C(O)— when used internally, wherein R^(X) and e are definedbelow. Examples of amido groups include alkylamido (such asalkylcarbonylamino or alkylcarbonylamino), (heterocycloaliphatic)amido,(heteroaralkyl)amido, (heteroaryl)amido, (heterocycloalkyl)alkylamido,arylamido, aralkylamido, (cycloalkyl)alkylamido, or cycloalkylamido.

As used herein, an “amino” group refers to —NR^(X)R^(Y) wherein each ofR^(X) and R^(Y) is independently hydrogen, alkyl, cycloaliphatic,(cycloaliphatic)aliphatic, aryl, araliphatic, heterocycloaliphatic,(heterocycloaliphatic)aliphatic, heteroaryl, carboxy, sulfanyl,sulfinyl, sulfonyl, (aliphatic)carbonyl, (cycloaliphatic)carbonyl,((cycloaliphatic)aliphatic)carbonyl, arylcarbonyl,(araliphatic)carbonyl, (heterocycloaliphatic)carbonyl,((heterocycloaliphatic)aliphatic)carbonyl, (heteroaryl)carbonyl, or(heteroaraliphatic)carbonyl, each of which being defined herein andbeing optionally substituted. Examples of amino groups includealkylamino, dialkylamino, or arylamino. When the term “amino” is not theterminal group (e.g., alkylcarbonylamino), it is represented by—NR^(X)—. R^(X) has the same meaning as defined above.

As used herein, an “aryl” group used alone or as part of a larger moietyas in “aralkyl”, “aralkoxy”, or “aryloxyalkyl” refers to monocyclic(e.g., phenyl); bicyclic (e.g., indenyl, naphthalenyl,tetrahydronaphthyl, tetrahydroindenyl); and tricyclic (e.g., fluorenyltetrahydrofluorenyl, or tetrahydroanthracenyl, anthracenyl) ring systemsin which the monocyclic ring system is aromatic or at least one of therings in a bicyclic or tricyclic ring system is aromatic. The bicyclicand tricyclic ring systems include benzofused 2-3 membered carbocyclicrings. For example, a benzofused group includes phenyl fused with two ormore C₄₋₈ carbocyclic moieties. An aryl is optionally substituted withone or more substituents including aliphatic [e.g., alkyl, alkenyl, oralkynyl]; cycloaliphatic; (cycloaliphatic)aliphatic;heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl;alkoxy; (cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy;heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl;heteroaroyl; amino; oxo (on a non-aromatic carbocyclic ring of abenzofused bicyclic or tricyclic aryl); nitro; carboxy; amido; acyl[e.g., aliphaticcarbonyl; (cycloaliphatic)carbonyl;((cycloaliphatic)aliphatic)carbonyl; (araliphatic)carbonyl;(heterocycloaliphatic)carbonyl;((heterocycloaliphatic)aliphatic)carbonyl; or(heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphaticsulfonyl oraminosulfonyl]; sulfinyl [e.g., aliphaticsulfinyl orcycloaliphaticsulfinyl]; sulfanyl [e.g., aliphaticsulfanyl]; cyano;halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamide;or carbamoyl. Alternatively, an aryl can be unsubstituted.

Non-limiting examples of substituted aryls include haloaryl [e.g.,mono-, di (such as p,m-dihaloaryl), and (trihalo)aryl]; (carboxy)aryl[e.g., (alkoxycarbonyl)aryl, ((aralkyl)carbonyloxy)aryl, and(alkoxycarbonyl)aryl]; (amido)aryl [e.g., (aminocarbonyl)aryl,(((alkylamino)alkyl)aminocarbonyl)aryl, (alkylcarbonyl)aminoaryl,(arylaminocarbonyl)aryl, and (((heteroaryl)amino)carbonyl)aryl];aminoaryl [e.g., ((alkylsulfonyl)amino)aryl or ((dialkyl)amino)aryl];(cyanoalkyl)aryl; (alkoxy)aryl; (sulfamoyl)aryl [e.g.,(aminosulfonyl)aryl]; (alkylsulfonyl)aryl; (cyano)aryl;(hydroxyalkyl)aryl; ((alkoxy)alkyl)aryl; (hydroxy)aryl,((carboxy)alkyl)aryl; (((dialkyl)amino)alkyl)aryl; (nitroalkyl)aryl;(((alkylsulfonyl)amino)alkyl)aryl; ((heterocycloaliphatic)carbonyl)aryl;((alkylsulfonyl)alkyl)aryl; (cyanoalkyl)aryl; (hydroxyalkyl)aryl;(alkylcarbonyl)aryl; alkylaryl; (trihaloalkyl)aryl;p-amino-m-alkoxycarbonylaryl; p-amino-m-cyanoaryl; p-halo-m-aminoaryl;or (m-(heterocycloaliphatic)-o-(alkyl))aryl.

As used herein, an “araliphatic” such as an “aralkyl” group refers to analiphatic group (e.g., a C₁₋₄ alkyl group) that is substituted with anaryl group. “Aliphatic,” “alkyl,” and “aryl” are defined herein. Anexample of an araliphatic such as an aralkyl group is benzyl.

As used herein, an “aralkyl” group refers to an alkyl group (e.g., aC₁₋₄ alkyl group) that is substituted with an aryl group. Both “alkyl”and “aryl” have been defined above. An example of an aralkyl group isbenzyl. An aralkyl is optionally substituted with one or moresubstituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl,including carboxyalkyl, hydroxyalkyl, or haloalkyl such astrifluoromethyl], cycloaliphatic [e.g., cycloalkyl or cycloalkenyl],(cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl,heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy,heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro,carboxy, alkoxycarbonyl, alkylcarbonyloxy, amido [e g, aminocarbonyl,alkylcarbonylamino, cycloalkylcarbonylamino,(cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino,(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,heteroarylcarbonylamino, or heteroaralkylcarbonylamino], cyano, halo,hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea,sulfamoyl, sulfamide, oxo, or carbamoyl.

As used herein, a “bicyclic ring system” includes 8-12 (e.g., 9, 10, or11) membered structures that form two rings, wherein the two rings haveat least one atom in common (e.g., 2 atoms in common). Bicyclic ringsystems include bicycloaliphatics (e.g., bicycloalkyl orbicycloalkenyl), bicycloheteroaliphatics, bicyclic aryls, and bicyclicheteroaryls.

As used herein, a “cycloaliphatic” group encompasses a “cycloalkyl”group and a “cycloalkenyl” group, each of which being optionallysubstituted as set forth below.

As used herein, a “cycloalkyl” group refers to a saturated carbocyclicmono- or bicyclic (fused or bridged) ring of 3-10 (e.g., 5-10) carbonatoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl,octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl,bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl,bicyclo[2.2.2]octyl, adamantyl, azacycloalkyl, or((aminocarbonyl)cycloalkyl)cycloalkyl. A “cycloalkenyl” group, as usedherein, refers to a non-aromatic carbocyclic ring of 3-10 (e.g., 4-8)carbon atoms having one or more double bonds. Examples of cycloalkenylgroups include cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl,cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl,cyclopentenyl, bicyclo[2.2.2]octenyl, or bicyclo[3.3.1]nonenyl. Acycloalkyl or cycloalkenyl group can be optionally substituted with oneor more substituents such as aliphatic [e.g., alkyl, alkenyl, oralkynyl], cycloaliphatic, (cycloaliphatic) aliphatic,heterocycloaliphatic, (heterocycloaliphatic) aliphatic, aryl,heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy,aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl,heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino,(cycloaliphatic)carbonylamino, ((cycloaliphatic)aliphatic)carbonylamino,(aryl)carbonylamino, (araliphatic)carbonylamino,(heterocycloaliphatic)carbonylamino,((heterocycloaliphatic)aliphatic)carbonylamino,(heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro,carboxy [e.g., HOOC—, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g.,(cycloaliphatic)carbonyl, ((cycloaliphatic) aliphatic)carbonyl,(araliphatic)carbonyl, (heterocycloaliphatic)carbonyl,((heterocycloaliphatic)aliphatic)carbonyl, or(heteroaraliphatic)carbonyl], cyano, halo, hydroxy, mercapto, sulfonyl[e.g., alkylsulfonyl and arylsulfonyl], sulfinyl [e.g., alkylsulfinyl],sulfanyl [e.g., alkylsulfanyl], sulfoxy, urea, thiourea, sulfamoyl,sulfamide, oxo, or carbamoyl.

As used herein, “cyclic moiety” includes cycloaliphatic,heterocycloaliphatic, aryl, or heteroaryl, each of which has beendefined previously.

As used herein, the term “heterocycloaliphatic” encompasses aheterocycloalkyl group and a heterocycloalkenyl group, each of whichbeing optionally substituted as set forth below.

As used herein, a “heterocycloalkyl” group refers to a 3-10 memberedmono- or bicylic (fused or bridged) (e.g., 5- to 10-membered mono- orbicyclic) saturated ring structure, in which one or more of the ringatoms is a heteroatom (e.g., N, O, S, or combinations thereof). Examplesof a heterocycloalkyl group include piperidyl, piperazyl,tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithianyl,1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl,octahydrobenzofuryl, octahydrochromenyl, octahydrothiochromenyl,octahydroindolyl, octahydropyrindinyl, decahydroquinolinyl,octahydrobenzo[b]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl,1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and2,6-dioxa-tricyclo[3.3.1.0^(3,7)]nonyl. A monocyclic heterocycloalkylgroup can be fused with a phenyl moiety such as tetrahydroisoquinoline.A “heterocycloalkenyl” group, as used herein, refers to a mono- orbicylic (e.g., 5- to 10-membered mono- or bicyclic) non-aromatic ringstructure having one or more double bonds, and wherein one or more ofthe ring atoms is a heteroatom (e.g., N, O, or S). Monocyclic andbicycloheteroaliphatics are numbered according to standard chemicalnomenclature.

A heterocycloalkyl or heterocycloalkenyl group can be optionallysubstituted with one or more substituents such as aliphatic [e.g.,alkyl, alkenyl, or alkynyl], cycloaliphatic, (cycloaliphatic)aliphatic,heterocycloaliphatic, (heterocycloaliphatic)aliphatic, aryl, heteroaryl,alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy,heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl,heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino,(cycloaliphatic)carbonylamino, ((cycloaliphatic)aliphatic)carbonylamino, (aryl)carbonylamino,(araliphatic)carbonylamino, (heterocycloaliphatic)carbonylamino,((heterocycloaliphatic) aliphatic)carbonylamino,(heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro,carboxy [e.g., HOOC—, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g.,(cycloaliphatic)carbonyl, ((cycloaliphatic) aliphatic)carbonyl,(araliphatic)carbonyl, (heterocycloaliphatic)carbonyl,((heterocycloaliphatic)aliphatic)carbonyl, or(heteroaraliphatic)carbonyl], nitro, cyano, halo, hydroxy, mercapto,sulfonyl [e.g., alkylsulfonyl or arylsulfonyl], sulfinyl [e.g.,alkylsulfinyl], sulfanyl [e.g., alkylsulfanyl], sulfoxy, urea, thiourea,sulfamoyl, sulfamide, oxo, or carbamoyl.

A “heteroaryl” group, as used herein, refers to a monocyclic, bicyclic,or tricyclic ring system having 4 to 15 ring atoms wherein one or moreof the ring atoms is a heteroatom (e.g., N, O, S, or combinationsthereof) and in which the monocyclic ring system is aromatic or at leastone of the rings in the bicyclic or tricyclic ring systems is aromatic.A heteroaryl group includes a benzofused ring system having 2 to 3rings. For example, a benzofused group includes benzo fused with one ortwo 4 to 8 membered heterocycloaliphatic moieties (e.g., indolizyl,indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, quinolinyl, or isoquinolinyl). Some examples ofheteroaryl are azetidinyl, pyridyl, 1H-indazolyl, furyl, pyrrolyl,thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl,isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine,dihydroindole, benzo[1,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl,indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl,quinazolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl,4H-quinolizyl, benzo-1,2,5-thiadiazolyl, or 1,8-naphthyridyl.

Without limitation, monocyclic heteroaryls include furyl, thiophenyl,2H-pyrrolyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4-H-pyranyl,pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl.Monocyclic heteroaryls are numbered according to standard chemicalnomenclature.

Without limitation, bicyclic heteroaryls include indolizyl, indolyl,isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl,quinolinyl, isoquinolinyl, indolizyl, isoindolyl, indolyl,benzo[b]furyl, bexo[b]thiophenyl, indazolyl, benzimidazyl,benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl, cinnolyl,phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl, or pteridyl.Bicyclic heteroaryls are numbered according to standard chemicalnomenclature.

A heteroaryl is optionally substituted with one or more substituentssuch as aliphatic [e.g., alkyl, alkenyl, or alkynyl]; cycloaliphatic;(cycloaliphatic)aliphatic; heterocycloaliphatic;(heterocycloaliphatic)aliphatic; aryl; heteroaryl; alkoxy;(cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy;(araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo(on a non-aromatic carbocyclic or heterocyclic ring of a bicyclic ortricyclic heteroaryl); carboxy; amido; acyl [e.g., aliphaticcarbonyl;(cycloaliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl;(araliphatic)carbonyl; (heterocycloaliphatic)carbonyl;((heterocycloaliphatic)aliphatic)carbonyl; or(heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphaticsulfonyl oraminosulfonyl]; sulfinyl [e.g., aliphaticsulfinyl]; sulfanyl [e.g.,aliphaticsulfanyl]; nitro; cyano; halo; hydroxy; mercapto; sulfoxy;urea; thiourea; sulfamoyl; sulfamide; or carbamoyl. Alternatively, aheteroaryl can be unsubstituted.

Non-limiting examples of substituted heteroaryls include(halo)heteroaryl [e.g., mono- and di-(halo)heteroaryl];(carboxy)heteroaryl [e.g., (alkoxycarbonyl)heteroaryl]; cyanoheteroaryl;aminoheteroaryl [e.g., ((alkylsulfonyl)amino)heteroaryland((dialkyl)amino)heteroaryl]; (amido)heteroaryl [e g,aminocarbonylheteroaryl, ((alkylcarbonyl)amino)heteroaryl,((((alkyl)amino)alkyl)aminocarbonyl)heteroaryl,(((heteroaryl)amino)carbonyl)heteroaryl,((heterocycloaliphatic)carbonyl)heteroaryl, and((alkylcarbonyl)amino)heteroaryl]; (cyanoalkyl)heteroaryl;(alkoxy)heteroaryl; (sulfamoyl)heteroaryl [e.g.,(aminosulfonyl)heteroaryl]; (sulfonyl)heteroaryl [e.g.,(alkylsulfonyl)heteroaryl]; (hydroxyalkyl)heteroaryl;(alkoxyalkyl)heteroaryl; (hydroxy)heteroaryl;((carboxy)alkyl)heteroaryl; [((dialkyl)amino)alkyl]heteroaryl;(heterocycloaliphatic)heteroaryl; (cycloaliphatic)heteroaryl;(nitroalkyl)heteroaryl; (((alkylsulfonyl)amino)alkyl)heteroaryl;((alkylsulfonyl)alkyl)heteroaryl; (cyanoalkyl)heteroaryl;(acyl)heteroaryl [e.g., (alkylcarbonyl)heteroaryl]; (alkyl)heteroaryl,and (halo alkyl)heteroaryl [e.g., trihaloalkylheteroaryl].

A “heteroaraliphatic” (such as a heteroaralkyl group) as used herein,refers to an aliphatic group (e.g., a C₁₋₄ alkyl group) that issubstituted with a heteroaryl group. “Aliphatic,” “alkyl,” and“heteroaryl” have been defined above.

A “heteroaralkyl” group, as used herein, refers to an alkyl group (e.g.,a C₁₋₄ alkyl group) that is substituted with a heteroaryl group. Both“alkyl” and “heteroaryl” have been defined above. A heteroaralkyl isoptionally substituted with one or more substituents such as alkyl(including carboxyalkyl, hydroxyalkyl, and haloalkyl such astrifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy,cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl,alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino,cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino,arylcarbonylamino, aralkylcarbonylamino,(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo,hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea,sulfamoyl, sulfamide, oxo, or carbamoyl.

As used herein, “cyclic moiety” includes cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl, each of which hasbeen defined previously.

As used herein, an “acyl” group refers to a formyl group or R^(X)—C(O)—(such as -alkyl-C(O)—, also referred to as “alkylcarbonyl”) where R^(X)and “alkyl” have been defined previously. Acetyl and pivaloyl areexamples of acyl groups.

As used herein, an “aroyl” or “heteroaroyl” refers to an aryl-C(O)— or aheteroaryl-C(O)—. The aryl and heteroaryl portion of the aroyl orheteroaroyl is optionally substituted as previously defined.

As used herein, an “alkoxy” group refers to an alkyl-O— group where“alkyl” has been defined previously.

As used herein, a “carbamoyl” group refers to a group having thestructure —O—CO—NR^(X)R^(Y) or —NR^(X)—CO—O—R^(Z) wherein R^(X) andR^(Y) have been defined above and R^(Z) can be aliphatic, aryl,araliphatic, heterocycloaliphatic, heteroaryl, or heteroaraliphatic.

As used herein, a “carboxy” group refers to —COOH, —COOR^(X), —OC(O)H,—OC(O)R^(X) when used as a terminal group; or —OC(O)— or —C(O)O— whenused as an internal group.

As used herein, a “haloaliphatic” group refers to an aliphatic groupsubstituted with 1, 2, or 3 halogen. For instance, the term haloalkylincludes the group —CF₃.

As used herein, a “mercapto” group refers to —SH.

As used herein, a “sulfo” group refers to —SO₃H or —SO₃R^(X) when usedterminally or —S(O)₃— when used internally.

As used herein, a “sulfamide” group refers to the structure—NR^(X)—S(O)₂—NR^(Y)R^(Z) when used terminally and —NR^(X)—S(O)₂—NR^(Y)—when used internally, wherein R^(X), e, and R^(Z) have been definedabove.

As used herein, a “sulfamoyl” group refers to the structure—S(O)₂—NR^(X)R^(Y) or —NR^(X)—S(O)₂—R^(Z) when used terminally; or—S(O)₂—NR^(X)— or —NR^(X)—S(O)₂— when used internally, wherein R^(X),R^(Y), and R^(Z) are defined above.

As used herein a “sulfanyl” group refers to —S—R^(X) when usedterminally and —S— when used internally, wherein R^(X) has been definedabove. Examples of sulfanyls include alkylsulfanyl.

As used herein a “sulfinyl” group refers to —S(O)—R^(X) when usedterminally and —S(O)— when used internally, wherein R^(X) has beendefined above.

As used herein, a “sulfonyl” group refers to —S(O)₂—R^(X) when usedterminally and —S(O)₂-when used internally, wherein R^(X) has beendefined above.

As used herein, a “sulfoxy” group refers to —O—SO—R^(X) or —SO—O—R^(X),when used terminally and —O—S(O)— or —S(O)—O— when used internally,where R^(X) has been defined above.

As used herein, a “halogen” or “halo” group refers to fluorine,chlorine, bromine or iodine.

As used herein, an “alkoxycarbonyl,” which is encompassed by the termcarboxy, used alone or in connection with another group refers to agroup such as alkyl-O—C(O)—.

As used herein, an “alkoxyalkyl” refers to an alkyl group such asalkyl-O-alkyl-, wherein alkyl has been defined above.

As used herein, a “carbonyl” refer to —C(O)—.

As used herein, an “oxo” refers to ═O.

As used herein, an “aminoalkyl” refers to the structure(R^(X)R^(Y))N-alkyl-.

As used herein, a “cyanoalkyl” refers to the structure (NC)-alkyl-.

As used herein, a “urea” group refers to the structure—NR^(X)—CO—NR^(Y)R^(Z) and a “thiourea” group refers to the structure—NR^(X)—CS—NR^(Y)R^(Z) when used terminally and —NR^(X)—CO—NR^(Y)- or—NR^(X)—CS—NR^(Y)— when used internally, wherein R^(X), R^(Y), and R^(Z)have been defined above.

As used herein, a “guanidino” group refers to the structure—N═C(N(R^(X)R^(Y)))N(R^(X)R^(Y)) wherein R^(X) and e have been definedabove.

As used herein, the term “amidino” group refers to the structure—C═(NR^(X))N(R^(X)R^(Y)) wherein R^(X) and e have been defined above.

In general, the term “vicinal” refers to the placement of substituentson a group that includes two or more carbon atoms, wherein thesubstituents are attached to adjacent carbon atoms.

In general, the term “geminal” refers to the placement of substituentson a group that includes two or more carbon atoms, wherein thesubstituents are attached to the same carbon atom.

The terms “terminally” and “internally” refer to the location of a groupwithin a substituent. A group is terminal when the group is present atthe end of the substituent not further bonded to the rest of thechemical structure. Carboxyalkyl, i.e., R^(X)O(O)C-alkyl is an exampleof a carboxy group used terminally. A group is internal when the groupis present in the middle of a substituent to at the end of thesubstituent bound to the rest of the chemical structure. Alkylcarboxy(e.g., alkyl-C(O)O— or alkyl-OC(O)—) and alkylcarboxyaryl (e.g.,alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxy groupsused internally.

As used herein, the term “amidino” group refers to the structure—C═(NR^(X))N(R^(X)R^(Y)) wherein R^(X) and R^(Y) have been definedabove.

As used herein, “cyclic group” includes mono-, bi-, and tri-cyclic ringsystems including cycloaliphatic, heterocycloaliphatic, aryl, orheteroaryl, each of which has been previously defined.

As used herein, a “bridged bicyclic ring system” refers to a bicyclicheterocyclicalipahtic ring system or bicyclic cycloaliphatic ring systemin which the rings are bridged. Examples of bridged bicyclic ringsystems include, but are not limited to, adamantanyl, norbornanyl,bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl,bicyclo[3.2.3]nonyl, 2-oxa-bicyclo[2.2.2]octyl,1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and2,6-dioxa-tricyclo[3.3.1.03,7]nonyl. A bridged bicyclic ring system canbe optionally substituted with one or more substituents such as alkyl(including carboxyalkyl, hydroxyalkyl, and haloalkyl such astrifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy,cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl,alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino,cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino,arylcarbonylamino, aralkylcarbonylamino,(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo,hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea,sulfamoyl, sulfamide, oxo, or carbamoyl.

As used herein, an “aliphatic chain” refers to a branched or straightaliphatic group (e.g., alkyl groups, alkenyl groups, or alkynyl groups).A straight aliphatic chain has the structure —[CH₂]_(v)—, where v is1-6. A branched aliphatic chain is a straight aliphatic chain that issubstituted with one or more aliphatic groups. A branched aliphaticchain has the structure —[CHQ]_(v)— where Q is hydrogen or an aliphaticgroup; however, Q shall be an aliphatic group in at least one instance.The term aliphatic chain includes alkyl chains, alkenyl chains, andalkynyl chains, where alkyl, alkenyl, and alkynyl are defined above.

The phrase “optionally substituted” is used interchangeably with thephrase “substituted or unsubstituted.” As described herein, compounds ofthe invention can optionally be substituted with one or moresubstituents, such as are illustrated generally above, or as exemplifiedby particular classes, subclasses, and species of the invention. Asdescribed herein, the variables R₁, R₂, R₃, and R₄, and other variablescontained therein formulae I encompass specific groups, such as alkyland aryl. Unless otherwise noted, each of the specific groups for thevariables R₁, R₂, R₃, and R₄, and other variables contained therein canbe optionally substituted with one or more substituents describedherein. Each substituent of a specific group is further optionallysubstituted with one to three of halo, cyano, oxoalkoxy, hydroxy, amino,nitro, aryl, haloalkyl, and alkyl. For instance, an alkyl group can besubstituted with alkylsulfanyl and the alkylsulfanyl can be optionallysubstituted with one to three of halo, cyano, oxoalkoxy, hydroxy, amino,nitro, aryl, haloalkyl, and alkyl. As an additional example, thecycloalkyl portion of a (cycloalkyl)carbonylamino can be optionallysubstituted with one to three of halo, cyano, alkoxy, hydroxy, nitro,haloalkyl, and alkyl. When two alkoxy groups are bound to the same atomor adjacent atoms, the two alkoxy groups can form a ring together withthe atom(s) to which they are bound.

In general, the term “substituted,” whether preceded by the term“optionally” or not, refers to the replacement of hydrogen radicals in agiven structure with the radical of a specified substituent. Specificsubstituents are described above in the definitions and below in thedescription of compounds and examples thereof. Unless otherwiseindicated, an optionally substituted group can have a substituent ateach substitutable position of the group, and when more than oneposition in any given structure can be substituted with more than onesubstituent selected from a specified group, the substituent can beeither the same or different at every position. A ring substituent, suchas a heterocycloalkyl, can be bound to another ring, such as acycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings shareone common atom. As one of ordinary skill in the art will recognize,combinations of substituents envisioned by this invention are thosecombinations that result in the formation of stable or chemicallyfeasible compounds.

The phrase “up to”, as used herein, refers to zero or any integer numberthat is equal or less than the number following the phrase. For example,“up to 3” means any one of 0, 1, 2, and 3.

The phrase “stable or chemically feasible,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and preferablytheir recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

As used herein, an effective amount is defined as the amount required toconfer a therapeutic effect on the treated patient, and is typicallydetermined based on age, surface area, weight, and condition of thepatient. The interrelationship of dosages for animals and humans (basedon milligrams per meter squared of body surface) is described byFreireich et al., Cancer Chemother. Rep., 50: 219 (1966). Body surfacearea may be approximately determined from height and weight of thepatient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley,N.Y., 537 (1970). As used herein, “patient” refers to a mammal,including a human.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. Additionally, unless otherwise stated, structuresdepicted herein are also meant to include compounds that differ only inthe presence of one or more isotopically enriched atoms. For example,compounds having the present structures except for the replacement ofhydrogen by deuterium or tritium, or the replacement of a carbon by a¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Suchcompounds are useful, for example, as analytical tools or probes inbiological assays.

Compounds

Compounds of the present invention are useful modulators of ABCtransporters and are useful in the treatment of ABC transport mediateddiseases.

Compounds

The present invention includes a compound of formula I,

or a pharmaceutically acceptable salt thereof, wherein:

each R′₁ is:

wherein:

m is 0-4;

R_(P) is optionally substituted C1-C6 aliphatic, wherein up to twocarbon units therein are optionally and independently replaced by —CO—,—CONR^(N)—, —CO₂—, —OCO—, —NR^(N)CO₂—, —O—, —OCONR^(N)—, —NR^(N)CO—,—S—, —SO—, —SO₂—, —NR^(N)—;

each R_(M) is independently —Z^(M)R₁₁, wherein each Z^(M) isindependently a bond or an optionally substituted branched or straightC₁₋₆ aliphatic chain wherein up to two carbon units of Z^(M) areoptionally and independently replaced by —CO—, —CONR^(N)—, —OO₂—, —OCO—,—CHR^(N)—, —NR^(N)CO₂—, —O—, —OCONR^(N)—, —NR^(N)CO—, —S—, —SO—, —SO₂—,—NR^(N)—;

each R₁₁ is independently R^(N), halo, —OH, —NH₂, —CN, —CF₃, or —OCF₃;

each R^(N) is independently hydrogen, an optionally substituted C₁₋₈aliphatic group, an optionally substituted cycloaliphatic, an optionallysubstituted heterocycloaliphatic, an optionally substituted aryl, or anoptionally substituted heteroaryl;

each R₁ is an optionally substituted C₁₋₆ aliphatic, an optionallysubstituted C₁₋₆ alkoxy, an optionally substituted C₃₋₁₀ cycloaliphatic,—CN, halo, or hydroxy;

each R₂ is hydrogen or an optionally substituted C₁₋₆ aliphatic;

each R₃ and R′₃ together with the carbon atom to which they are attachedform an optionally substituted C₃₋₇ cycloaliphatic or an optionallysubstituted heterocycloaliphatic;

each R₄ is an optionally substituted aryl; and

n is 0-3.

Embodiments

Substituent R′₁

In one embodiment, R′₁ is selected from:

In one embodiment, R′₁ is selected from:

In one embodiment, R′₁ is:

In another embodiment, R′₁ is:

In another embodiment, R′₁ is:

In another embodiment, R′₁ is:

In another embodiment, R′₁ is selected from:

In another embodiment, R′₁ is selected from:

In one embodiment, R′₁ is:

In another embodiment, R′₁ is:

In another embodiment, R′₁ is:

In another embodiment, R′₁ is:

Substituent R₁

Each R₁ is independently an optionally substituted C₁₋₆ aliphatic, anoptionally substituted C₁₋₆ alkoxy, an optionally substituted C₃₋₁₀membered cycloaliphatic, —CN, halo, or hydroxy.

In some embodiments, one R₁ is an optionally substituted C₁₋₆ aliphatic.In several examples, one R₁ is an optionally substituted C₁₋₆ alkyl, anoptionally substituted C₂₋₆ alkenyl, or an optionally substituted C₂₋₆alkynyl. In several examples, one R₁ is C₁₋₆ alkyl, C₂₋₆ alkenyl, orC₂₋₆ alkynyl.

In several embodiments, R₁ is halo.

In several embodiments, R₁ is —CN.

In some embodiments, R₁ is methyl, ethyl, i-propyl, t-butyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, allyl, F, Cl, methoxy,ethoxy, i-propoxy, t-butoxy, or CF₃. In several examples, R₁ is methyl,or methoxy. Or, R₁ can be methyl.

Substituent R₂

R₂ can be hydrogen. Or, R₂ can be an optionally substituted C₁₋₆aliphatic.

In several embodiments, R₂ is hydrogen.

Substituents R₃ and R′₃

Each R₃ and R′₃ together with the carbon atom to which they are attachedform a C₃₋₇ cycloaliphatic or a heterocycloaliphatic, each of which isoptionally substituted with 1, 2, or 3 substituents.

In several embodiments, R₃ and R′₃ together with the carbon atom towhich they are attached form a C₃₋₇ cycloaliphatic or a C₃₋₇heterocycloaliphatic, each of which is optionally substituted with 1, 2,or 3 of —Z^(B)R₂, wherein each Z^(B) is independently a bond, or anoptionally substituted branched or straight C₁₋₄ aliphatic chain whereinup to two carbon units of Z^(B) are optionally and independentlyreplaced by —CO—, —CONR^(B)—, —CO₂—, —OCO—, —NR^(B)CO₂—, —O—,—OCONR^(B)—, —NR^(B)CO—, —S—, —SO—, —SO₂—, or —NR^(B)—; each R₇ isindependently R^(B), halo, —OH, —NH₂, —NO₂, —CN, —CF₃, or —OCF₃; andeach R^(B) is independently hydrogen, an optionally substituted C₁₋₈aliphatic group, an optionally substituted cycloaliphatic, an optionallysubstituted heterocycloaliphatic, an optionally substituted aryl, or anoptionally substituted heteroaryl.

In several embodiments, R₃ and R′₃ together with the carbon atom towhich they are attached form a 3, 4, 5, or 6 membered cycloaliphaticthat is optionally substituted with 1, 2, or 3 substituents. In severalexamples, R₃, R′₃, and the carbon atom to which they are attached forman optionally substituted cyclopropyl group. In several alternativeexamples, R₃, R′₃, and the carbon atom to which they are attached forman optionally substituted cyclobutyl group. In several other examples,R₃, R′₃, and the carbon atom to which they are attached form anoptionally substituted cyclopentyl group. In other examples, R₃, R′₃,and the carbon atom to which they are attached form an optionallysubstituted cyclohexyl group. In more examples, R₃ and R′₃ together withthe carbon atom to which they are attached form an unsubstitutedcyclopropyl.

In some embodiments, R₃ and R′₃ together with the carbon atom to whichthey are attached form an unsubstituted C₃₋₇ cycloaliphatic. In severalexamples, R₃ and R′₃ together with the carbon atom to which they areattached form an unsubstituted cyclopropyl, an unsubstitutedcyclopentyl, or an unsubstituted cyclohexyl. In some embodiments, R₃ andR′₃ together with the carbon atom to which they are attached form anunsubstituted cyclopropyl.

Substituent R₄

In several embodiments, R₄ is an aryl having 6 to 10 atoms (e.g., 7 to10 atoms) optionally substituted with 1, 2, or 3 substituents. Examplesof R₄ include optionally substituted benzene, naphthalene, or indene.Or, examples of R₄ can be optionally substituted phenyl, optionallysubstituted naphthyl, or optionally substituted indenyl.

In some embodiments, R₄ is an aryl, optionally substituted with 1, 2, or3 of —Z^(C)R₈. In some embodiments, R₄ is phenyl optionally substitutedwith 1, 2, or 3 of —Z^(C)R₈. Each Z^(C) is independently a bond or anoptionally substituted branched or straight C₁₋₆ aliphatic chain whereinup to two carbon units of Z^(C) are optionally and independentlyreplaced by —CO—, —CS—, —CONR^(C)—, —CONR^(C)NR^(C)—, —CO₂—, —OCO—,—NR^(C)CO₂—, —O—, —NR^(C)CONR^(C)—, —OCONR^(C)—, —NR^(C)NR^(C)—,—NR^(C)CO—, —S—, —SO—, —SO₂—, —NR^(C)—, —SO₂NR^(C)—, —NR^(C)SO₂—, or—NR^(C)SO₂NR^(C)—. Each R₈ is independently R^(C), halo, —OH, —NH₂,—NO₂, —CN, —CF₃, or —OCF₃. Each R^(C) is independently hydrogen, anoptionally substituted C₁₋₈ aliphatic group, an optionally substitutedcycloaliphatic, an optionally substituted heterocycloaliphatic, anoptionally substituted aryl, or an optionally substituted heteroaryl.

In some embodiments, two occurrences of —Z^(C)R₈, taken together withcarbons to which they are attached, form a 4-8 membered saturated,partially saturated, or aromatic ring with up to 3 ring atomsindependently selected from the group consisting of 0, NH, NR^(C), andS; wherein R^(C) is defined herein.

In several embodiments, R₄ is selected from:

In one embodiment, R₄ is (a). Or, R₄ is (b). In some embodiments, R₄ is(c). In other embodiments, R₄ is (d). In some embodiments, R₄ is (e). Insome embodiments, R₄ is (f). In some embodiments, R₄ is (g). In someembodiments, R₄ is (h). In some embodiments, R₄ is (i). In someembodiments, R₄ is (i). In some embodiments, R₄ is (k).

In some embodiments, the present invention relates to compounds offormula I and the attendant definitions, wherein m is 0-2. In someembodiments, m is 1. In some embodiments, m is 0.

In some embodiments, the present invention relates to compounds offormula I and the attendant definitions, wherein R_(M) is independently—Z^(M)R_(ii), wherein each Z^(M) is independently a bond or C₁₋₄ alkylchain wherein up to two carbon units of Z^(M) are optionally andindependently replaced by —CO—, —CONR^(N)—, —CHR^(N)—, —CO₂—, —OCO—,—NR^(N)CO₂—, —O—, —OCONR^(N)—, —NR^(N)CO—, —S—, —SO—, —SO₂—, or—NR^(N)—. In other embodiments, R_(M) is independently —Z^(M)R_(ii),wherein each Z^(M) is independently a bond or C₁₋₄ alkyl chain whereinup to two carbon units of Z^(M) are optionally and independentlyreplaced by —CONR^(N)—, —OO₂—, —O—, —CHR^(N)—, or —NR^(N)—.

In some embodiments, the present invention relates to compounds offormula I and the attendant definitions, wherein R₁₁ is independentlyR^(N), halo, —OH, —NH₂, or —CN. In some embodiments, R^(N) isindependently hydrogen, C1-C6 aliphatic, or C3-C6 cycloaliphatic.

In some embodiments, the present invention relates to compounds offormula I and the attendant definitions, wherein R^(M) is absent or isselected from —CH₂OH, NHC(O)Me, Et, Me, —CH₂C(O)OH, —CH₂C(O)OMe,—CH₂CH₂OH, —C(O)OH, halo, OH, C(O)NHMe, C(O)NH₂, —CH₂CH(OH)CH₂OH, NH₂,OMe, CH₂CN, CH₂CH₂SO₂CH₃, CH₂CONHCN, CONMe₂, or CN.

In some embodiments, the present invention relates to compounds offormula I and the attendant definitions, wherein R^(P) is C1-C6aliphatic, wherein up to two carbon units therein are optionally andindependently replaced by —CO—, —CS—, —CONR^(N)—, —CO₂—, —NR^(N)CO₂—,—O—, —S—, —SO—, —SO₂—, or —NR^(N)—.

In some embodiments, the present invention relates to compounds offormula I and the attendant definitions, wherein n is 1-2. In someembodiments, n is 1.

Exemplary Compound Families

In another aspect, the present invention includes compounds of formula Iand the attendant definitions, wherein the compounds have formula II:

or a pharmaceutically acceptable salt thereof,

wherein:

R′₁ is selected from:

n is 0-2;

m is 0-4;

R₁ is C1-6 aliphatic, halo, or —CN; and

R₄ is selected from:

In some embodiments of formula II, n is 1. Or, n is 2.

In some embodiments, R₁ is selected from the group consisting of methyl,ethyl, i-propyl, t-butyl, F, Cl, or —CN. Or, R₁ is methyl. In oneembodiment, n is 1 and R₁ is 5-methyl. In one embodiment, n is 1 and R₁is 4-methyl. In one embodiment, n is 2 and one R₁ is 4-methyl and theother R₁ is 5-methyl.

In another aspect, the present invention includes compounds of formulaII and the attendant definitions, wherein the compounds have formulaIIA:

or a pharmaceutically acceptable salt thereof,

wherein:

R′₁ is:

n is 0-2;

m is 0-4;

R₁ is C1-6 aliphatic, halo, or —CN; and

R₄ is selected from:

In one embodiment of formula IIA, R′₁ is selected from:

In one embodiment of formula IIA, R′₁ is:

In another embodiment of formula IIA, R′₁ is:

In another embodiment of formula IIA, R′₁ is:

In another embodiment of formula IIA, R′₁ is:

In some embodiments, the present invention includes compounds of formulaII and the attendant definitions, wherein the compounds have formulaIIB:

or a pharmaceutically acceptable salt thereof,

wherein:

R′₁ is:

m is 0-4;

n is 0-2;

R₁ is C1-6 aliphatic, halo, or —CN; and

R₄ is selected from:

In another embodiment of formula IIB, R′₁ is selected from:

In one embodiment of formula IIB, R′₁ is:

In another embodiment of formula IIB, R′₁ is:

In another embodiment of formula IIB, R′₁ is:

In another embodiment of formula IIB, R′₁ is:

In some embodiments, the present invention includes compounds of formulaI and the attendant definitions, wherein the compounds have formula III:

or a pharmaceutically acceptable salt thereof,

wherein:

R′₁ is selected from:

m is 0-4;

R₁ is C1-6 aliphatic, halo, or —CN; and

R₄ is selected from:

In one embodiment of compounds of formula III, R₁ is methyl. In oneembodiment of compounds of formula III, R₁ is Cl. In one embodiment ofcompounds of formula III, R₁ is —CN.

In some embodiments, the present invention includes compounds of formulaIII and the attendant definitions, wherein the compounds have formulaIIIA:

or a pharmaceutically acceptable salt thereof,

wherein:

R′₁ is:

m is 0-4;

R₁ is C1-6 aliphatic, halo, or —CN; and

R₄ is selected from:

In one embodiment of compounds of formula IIIA, R₁ is methyl. In oneembodiment of compounds of formula IIIA, R₁ is Cl. In one embodiment ofcompounds of formula IIIA, R₁ is —CN.

In some embodiments, the present invention includes compounds of formulaIII and the attendant definitions, wherein the compounds have formulaIIIB:

or a pharmaceutically acceptable salt thereof,

wherein:

R′₁ is:

m is 0-4;

R₁ is C1-6 aliphatic, halo, or —CN; and

R₄ is selected from:

In one embodiment of compounds of formula IIIB, R₁ is methyl. In oneembodiment of compounds of formula IIIB, R₁ is Cl. In one embodiment ofcompounds of formula IIIB, R₁ is —CN.

In some embodiments, the present invention includes compounds of formulaI and the attendant definitions, wherein the compounds have formula IV:

or a pharmaceutically acceptable salt thereof,

wherein:

R′₁ is selected from:

m is 0-4;

R₁ is C1-6 aliphatic, halo, or —CN; and

R₄ is selected from:

In one embodiment of compounds of formula IV, R₁ is methyl. In oneembodiment of compounds of formula IV, R₁ is Cl. In one embodiment ofcompounds of formula IV, R₁ is —CN.

In some embodiments, the present invention includes compounds of formulaIV and the attendant definitions, wherein the compounds have formula WA:

or a pharmaceutically acceptable salt thereof,

wherein:

R′₁ is:

m is 0-4;

R₁ is C1-6 aliphatic, halo, or —CN; and

R₄ is selected from:

In one embodiment of compounds of formula IVA, R₁ is methyl. In oneembodiment of compounds of formula IVA, R₁ is Cl. In one embodiment ofcompounds of formula IVA, R₁ is —CN.

In some embodiments, the present invention includes compounds of formulaIV and the attendant definitions, wherein the compounds have formulaIVB:

or a pharmaceutically acceptable salt thereof,

wherein:

R′₁ is:

m is 0-4;

R₁ is C1-6 aliphatic, halo, or —CN; and

R₄ is selected from:

In one embodiment of compounds of formula IVB, R₁ is methyl. In oneembodiment of compounds of formula IVB, R₁ is Cl. In one embodiment ofcompounds of formula IVB, R₁ is —CN.

In some embodiments, the present invention includes compounds of formulaI and the attendant definitions, wherein the compounds have formula V:

or a pharmaceutically acceptable salt thereof,

wherein:

R′₁ is selected from:

m is 0-4;

R₁ is C1-6 aliphatic, halo, or —CN; and

R₄ is selected from:

In one embodiment of compounds of formula V, R₁ is methyl. In oneembodiment of compounds of formula V, R₁ is Cl. In one embodiment ofcompounds of formula V, R₁ is —CN.

In some embodiments, the present invention includes compounds of formulaV and the attendant definitions, wherein the compounds have formula VA:

or a pharmaceutically acceptable salt thereof,

wherein:

R′₁ is:

m is 0-4;

R₁ is C1-6 aliphatic, halo, or —CN; and

R₄ is selected from:

In one embodiment of compounds of formula VA, R₁ is methyl. In oneembodiment of compounds of formula VA, R₁ is Cl. In one embodiment ofcompounds of formula VA, R₁ is —CN.

In some embodiments, the present invention includes compounds of formulaV and the attendant definitions, wherein the compounds have formula VB:

or a pharmaceutically acceptable salt thereof,

wherein:

R′₁ is:

m is 0-4;

R₁ is C1-6 aliphatic, halo, or —CN; and

R₄ is selected from:

In one embodiment of compounds of formula VB, R₁ is methyl. In oneembodiment of compounds of formula VB, R₁ is Cl. In one embodiment ofcompounds of formula VB, R₁ is —CN.

In another aspect, the present invention includes compounds of formulaVI:

or a pharmaceutically acceptable salt thereof, wherein:

R′₁ is:

m is 0-4;

R_(P) is optionally substituted C1-C6 aliphatic, wherein up to twocarbon units therein are optionally and independently replaced by —CO—,—CONR^(N)—, —CO₂—, —OCO—, —NR^(N)CO₂—, —O—, —OCONR^(N)—, —NR^(N)CO—,—S—, —SO—, —SO₂—, —NR^(N)—;

R_(M) is independently —Z^(M)R₁₁, wherein each Z^(M) is independently abond or an optionally substituted branched or straight C₁₋₆ aliphaticchain wherein up to two carbon units of Z^(M) are optionally andindependently replaced by —CO—, —CONR^(N)—, —CO₂—, —OCO—, —CHR^(N)—,—NR^(N)CO₂—, —O—, —OCONR^(N)—, —NR^(N)CO—, —S—, —SO—, —SO₂—, —NR^(N)—;

R₁₁ is independently R^(N), halo, —OH, —NH₂, —CN, —CF₃, or —OCF₃;

R^(N) is independently hydrogen, an optionally substituted C₁₋₆aliphatic group, an optionally substituted cycloaliphatic, an optionallysubstituted heterocycloaliphatic, an optionally substituted aryl, or anoptionally substituted heteroaryl;

R₁ is an optionally substituted C₁₋₆ aliphatic, an optionallysubstituted C₁₋₆ alkoxy, an optionally substituted C₃₋₁₀ cycloaliphatic,—CN, halo, or hydroxy;

R₂ is hydrogen or an optionally substituted C₁₋₆ aliphatic;

R₃ and R′₃ together with the carbon atom to which they are attached forman optionally substituted C₃₋₇ cycloaliphatic or an optionallysubstituted heterocycloaliphatic;

R₄ is an optionally substituted aryl; and

n is 0-3.

In one embodiment of compounds of formula VI, R₄ is selected from:

In one embodiment of compounds of formula VI, R₄ is (b).

In one embodiment of compounds of formula VI, R₁ is methyl.

In some embodiments, the present invention includes compounds of formulaVI and the attendant definitions, wherein the compounds have formulaVIA:

or a pharmaceutically acceptable salt thereof,

wherein:

R′₁ is selected from:

m is 0-4;

R₁ is C1-6 aliphatic, halo, or —CN; and

R₄ is selected from:

In one embodiment of compounds of formula VIA, R₁ is methyl.

In one embodiment of compounds of formula VIA, R′₁ is:

In one embodiment of compounds of formula VIA, R′₁ is:

In some embodiments, the present invention includes compounds of formulaVI and the attendant definitions, wherein the compounds have formulaVIB:

or a pharmaceutically acceptable salt thereof,

wherein:

R′₁ is selected from:

m is 0-4;

R₁ is C1-6 aliphatic, halo, or —CN; and

R₄ is selected from:

In one embodiment of compounds of formula VIB, R₁ is methyl.

Exemplary compounds of the present invention include, but are notlimited to, those illustrated in Table 1 below.

TABLE 1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

Synthetic Schemes

Compounds of the invention may be prepared by known methods or asillustrated in the schemes below.

Formulations, Administrations, and Uses Pharmaceutically AcceptableCompositions

Accordingly, in another aspect of the present invention,pharmaceutically acceptable compositions are provided, wherein thesecompositions comprise any of the compounds as described herein, andoptionally comprise a pharmaceutically acceptable carrier, adjuvant orvehicle. In certain embodiments, these compositions optionally furthercomprise one or more additional therapeutic agents.

It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable derivative or a prodrug thereof. Accordingto the present invention, a pharmaceutically acceptable derivative or aprodrug includes, but is not limited to, pharmaceutically acceptablesalts, esters, salts of such esters, or any other adduct or derivativewhich upon administration to a patient in need is capable of providing,directly or indirectly, a compound as otherwise described herein, or ametabolite or residue thereof

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge, et al. describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of thepresent invention additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, preservatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. Remington: TheScience and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy,Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia ofPharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan,1988-1999, Marcel Dekker, New York, the contents of each of which isincorporated by reference herein, disclose various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, or potassiumsorbate, partial glyceride mixtures of saturated vegetable fatty acids,water, salts or electrolytes, such as protamine sulfate, disodiumhydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zincsalts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, woolfat, sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients such as cocoa butter andsuppository waxes; oils such as peanut oil, cottonseed oil; saffloweroil; sesame oil; olive oil; corn oil and soybean oil; glycols; such apropylene glycol or polyethylene glycol; esters such as ethyl oleate andethyl laurate; agar; buffering agents such as magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releasingagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

In another aspect, the present invention relates to a pharmaceuticalcomposition comprising (i) a compound of the present invention; and (ii)a pharmaceutically acceptable carrier. In another embodiment, thecomposition further comprises an additional agent selected from amucolytic agent, bronchodialator, an anti-biotic, an anti-infectiveagent, an anti-inflammatory agent, CFTR corrector, or a nutritionalagent. In another embodiment, the composition further comprises anadditional agent selected from compounds disclosed in U.S. patentapplication Ser. No. 11/165,818, published as U.S. Published PatentApplication No. 2006/0074075, filed Jun. 24, 2005, and herebyincorporated by reference in its entirety. In another embodiment, thecomposition further comprisesN-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide.These compositions are useful for treating the diseases described belowincluding cystic fibrosis. These compositions are also useful in thekits described below.

Uses of Compounds and Pharmaceutically Acceptable Compositions

In yet another aspect, the present invention provides a method oftreating a condition, disease, or disorder implicated by CFTR activity.In certain embodiments, the present invention provides a method oftreating a condition, disease, or disorder implicated by a deficiency ofCFTR activity, the method comprising administering a compositioncomprising a compound of the present invention to a subject, preferablya mammal, in need thereof

In certain preferred embodiments, the present invention provides amethod of treating Cystic fibrosis, Hereditary emphysema, Hereditaryhemochromatosis, Coagulation-Fibrinolysis deficiencies, such as ProteinC deficiency, Type 1 hereditary angioedema, Lipid processingdeficiencies, such as Familial hypercholesterolemia, Type 1chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, suchas I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses,Sandhof/Tay-Sachs, Crigler-Najjar type II,Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus, Laron dwarfism,Myleoperoxidase deficiency, Primary hypoparathyroidism, Melanoma,Glycanosis CDG type 1, Hereditary emphysema, Congenital hyperthyroidism,Osteogenesis imperfecta, Hereditary hypofibrinogenemia, ACT deficiency,Diabetes insipidus (DI), Neurophyseal DI, Neprogenic DI, Charcot-MarieTooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerativediseases such as Alzheimer's disease, Parkinson's disease, Amyotrophiclateral sclerosis, Progressive supranuclear plasy, Pick's disease,several polyglutamine neurological disorders such as Huntington,Spinocerebullar ataxia type I, Spinal and bulbar muscular atrophy,Dentatorubal pallidoluysian, and Myotonic dystrophy, as well asSpongiform encephalopathies, such as Hereditary Creutzfeldt-Jakobdisease (due to Prion protein processing defect), Fabry disease,Straussler-Scheinker disease, secretory diarrhea, polycystic kidneydisease, chronic obstructive pulmonary disease (COPD), dry eye disease,and Sjögren's Syndrome, comprising the step of administering to saidmammal an effective amount of a composition comprising a compound of thepresent invention or a preferred embodiment thereof as set forth above.

According to an alternative preferred embodiment, the present inventionprovides a method of treating cystic fibrosis comprising the step ofadministering to said mammal a composition comprising the step ofadministering to said mammal an effective amount of a compositioncomprising a compound of the present invention or a preferred embodimentthereof as set forth above.

According to the invention an “effective amount” of the compound orpharmaceutically acceptable composition is that amount effective fortreating or lessening the severity of one or more of Cystic fibrosis,Hereditary emphysema, Hereditary hemochromatosis,Coagulation-Fibrinolysis deficiencies, such as Protein C deficiency,Type 1 hereditary angioedema, Lipid processing deficiencies, such asFamilial hypercholesterolemia, Type 1 chylomicronemia,Abetalipoproteinemia, Lysosomal storage diseases, such as I-celldisease/Pseudo-Hurler, Mucopolysaccharidoses, Sandhof/Tay-Sachs,Crigler-Najjar type II, Polyendocrinopathy/Hyperinsulemia, Diabetesmellitus, Laron dwarfism, Myleoperoxidase deficiency, Primaryhypoparathyroidism, Melanoma, Glycanosis CDG type 1, Hereditaryemphysema, Congenital hyperthyroidism, Osteogenesis imperfecta,Hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI),Neurophyseal DI, Neprogenic DI, Charcot-Marie Tooth syndrome,Perlizaeus-Merzbacher disease, neurodegenerative diseases such asAlzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis,Progressive supranuclear plasy, Pick's disease, several polyglutamineneurological disorders asuch as Huntington, Spinocerebullar ataxia typeI, Spinal and bulbar muscular atrophy, Dentatorubal pallidoluysian, andMyotonic dystrophy, as well as Spongiform encephalopathies, such asHereditary Creutzfeldt-Jakob disease, Fabry disease,Straussler-Scheinker disease, secretory diarrhea, polycystic kidneydisease, chronic obstructive pulmonary disease (COPD), dry eye disease,and Sjögren's Syndrome.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of oneor more of Cystic fibrosis, Hereditary emphysema, Hereditaryhemochromatosis, Coagulation-Fibrinolysis deficiencies, such as ProteinC deficiency, Type 1 hereditary angioedema, Lipid processingdeficiencies, such as Familial hypercholesterolemia, Type 1chylomicronemia, Abetalipoproteinemia, Lysosomal storage diseases, suchas I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses,Sandhof/Tay-Sachs, Crigler-Najjar type II,Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus, Laron dwarfism,Myleoperoxidase deficiency, Primary hypoparathyroidism, Melanoma,Glycanosis CDG type 1, Hereditary emphysema, Congenital hyperthyroidism,Osteogenesis imperfecta, Hereditary hypofibrinogenemia, ACT deficiency,Diabetes insipidus (DI), Neurophyseal DI, Neprogenic DI, Charcot-MarieTooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerativediseases such as Alzheimer's disease, Parkinson's disease, Amyotrophiclateral sclerosis, Progressive supranuclear plasy, Pick's disease,several polyglutamine neurological disorders asuch as Huntington,Spinocerebullar ataxia type I, Spinal and bulbar muscular atrophy,Dentatorubal pallidoluysian, and Myotonic dystrophy, as well asSpongiform encephalopathies, such as Hereditary Creutzfeldt-Jakobdisease, Fabry disease, Straussler-Scheinker disease, secretorydiarrhea, polycystic kidney disease, chronic obstructive pulmonarydisease (COPD), dry eye disease, and Sjögren's Syndrome.

The exact amount required will vary from subject to subject, dependingon the species, age, and general condition of the subject, the severityof the infection, the particular agent, its mode of administration, andthe like. The compounds of the invention are preferably formulated indosage unit form for ease of administration and uniformity of dosage.The expression “dosage unit form” as used herein refers to a physicallydiscrete unit of agent appropriate for the patient to be treated. Itwill be understood, however, that the total daily usage of the compoundsand compositions of the present invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific effective dose level for any particular patient or organismwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms are prepared by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

As described generally above, the compounds of the invention are usefulas modulators of CFTR. Thus, without wishing to be bound by anyparticular theory, the compounds and compositions are particularlyuseful for treating or lessening the severity of a disease, condition,or disorder where hyperactivity or inactivity of CFTR is implicated inthe disease, condition, or disorder. When hyperactivity or inactivity ofan CFTR is implicated in a particular disease, condition, or disorder,the disease, condition, or disorder may also be referred to as an“CFTR-mediated disease, condition or disorder”. Accordingly, in anotheraspect, the present invention provides a method for treating orlessening the severity of a disease, condition, or disorder wherehyperactivity or inactivity of CFTR is implicated in the disease state.

The activity of a compound utilized in this invention as a modulator ofCFTR may be assayed according to methods described generally in the artand in the Examples herein.

It will also be appreciated that the compounds and pharmaceuticallyacceptable compositions of the present invention can be employed incombination therapies, that is, the compounds and pharmaceuticallyacceptable compositions can be administered concurrently with, prior to,or subsequent to, one or more other desired therapeutics or medicalprocedures. The particular combination of therapies (therapeutics orprocedures) to employ in a combination regimen will take into accountcompatibility of the desired therapeutics and/or procedures and thedesired therapeutic effect to be achieved. It will also be appreciatedthat the therapies employed may achieve a desired effect for the samedisorder (for example, an inventive compound may be administeredconcurrently with another agent used to treat the same disorder), orthey may achieve different effects (e.g., control of any adverseeffects). As used herein, additional therapeutic agents that arenormally administered to treat or prevent a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated”.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The compounds of this invention or pharmaceutically acceptablecompositions thereof may also be incorporated into compositions forcoating an implantable medical device, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Accordingly, the presentinvention, in another aspect, includes a composition for coating animplantable device comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. In still anotheraspect, the present invention includes an implantable device coated witha composition comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. Suitable coatingsand the general preparation of coated implantable devices are describedin U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings aretypically biocompatible polymeric materials such as a hydrogel polymer,polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylacticacid, ethylene vinyl acetate, and mixtures thereof. The coatings mayoptionally be further covered by a suitable topcoat of fluorosilicone,polysaccarides, polyethylene glycol, phospholipids or combinationsthereof to impart controlled release characteristics in the composition.

Another aspect of the invention relates to modulating CFTR activity in abiological sample or a patient (e.g., in vitro or in vivo), which methodcomprises administering to the patient, or contacting said biologicalsample with a compound of formula I or a composition comprising saidcompound. The term “biological sample”, as used herein, includes,without limitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof

Modulation of CFTR activity in a biological sample is useful for avariety of purposes that are known to one of skill in the art. Examplesof such purposes include, but are not limited to, the study of CFTRactivity in biological and pathological phenomena and the comparativeevaluation of new modulators of CFTR activity.

In yet another embodiment, a method of modulating activity of an anionchannel in vitro or in vivo, is provided comprising the step ofcontacting said channel with a compound of the present invention. Inpreferred embodiments, the anion channel is a chloride channel or abicarbonate channel. In other preferred embodiments, the anion channelis a chloride channel.

According to an alternative embodiment, the present invention provides amethod of increasing the number of functional CFTR in a membrane of acell, comprising the step of contacting said cell with a compound of thepresent invention. The term “functional CFTR” as used herein means anCFTR activity that is capable of transport activity.

According to another preferred embodiment, the activity of the CFTRactivity is measured by measuring the transmembrane voltage potential.Means for measuring the voltage potential across a membrane in thebiological sample may employ any of the known methods in the art, suchas optical membrane potential assay or other electrophysiologicalmethods.

The optical membrane potential assay utilizes voltage-sensitive FRETsensors described by Gonzalez and Tsien (See Gonzalez, J. E. and R. Y.Tsien (1995) “Voltage sensing by fluorescence resonance energy transferin single cells” Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y.Tsien (1997) “Improved indicators of cell membrane potential that usefluorescence resonance energy transfer” Chem Biol 4(4): 269-77) incombination with instrumentation for measuring fluorescence changes suchas the Voltage/Ion Probe Reader (VIPR) (See Gonzalez, J. E., K. Oades,et al. (1999) “Cell-based assays and instrumentation for screeningion-channel targets” Drug Discov Today 4(9): 431-439).

These voltage sensitive assays are based on the change in fluorescenceresonant energy transfer (FRET) between the membrane-soluble,voltage-sensitive dye, DiSBAC₂(3), and a fluorescent phospholipid,CC2-DMPE, which is attached to the outer leaflet of the plasma membraneand acts as a FRET donor. Changes in membrane potential (V_(m)) causethe negatively charged DiSBAC₂(3) to redistribute across the plasmamembrane and the amount of energy transfer from CC2-DMPE changesaccordingly. The changes in fluorescence emission can be monitored usingVIPR™ II, which is an integrated liquid handler and fluorescent detectordesigned to conduct cell-based screens in 96- or 384-well microtiterplates.

In another aspect the present invention provides a kit for use inmeasuring the activity of a CFTR activity or a fragment thereof in abiological sample in vitro or in vivo comprising (i) a compositioncomprising a compound of the present invention; and (ii) instructionsfor a.) contacting the composition with the biological sample and b.)measuring activity of said CFTR activity or a fragment thereof. In oneembodiment, the kit further comprises instructions for a.) contacting anadditional composition with the biological sample; b.) measuring theactivity of said CFTR activity or a fragment thereof in the presence ofsaid additional compound, and c.) comparing the activity of the CFTRactivity in the presence of the additional compound with the density ofthe CFTR activity in the presence of a compound of the presentinvention.

PREPARATIONS AND EXAMPLES A.1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid

Step a: 2,2-Difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester

A solution of 5-bromo-2,2-difluoro-benzo[1,3]dioxole (11.8 g, 50.0 mmol)and tetrakis(triphenylphosphine)palladium (0) [Pd(PPh₃)₄, 5.78 g, 5.00mmol] in methanol (20 mL) containing acetonitrile (30 mL) andtriethylamine (10 mL) was stirred under a carbon monoxide atmosphere (55PSI) at 75° C. (oil bath temperature) for 15 hours. The cooled reactionmixture was filtered and the filtrate was evaporated to dryness. Theresidue was purified by silica gel column chromatography to give crude2,2-difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester (11.5 g),which was used directly in the next step.

Step b: (2,2-Difluoro-benzo[1,3]dioxol-5-yl)-methanol

Crude 2,2-difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester(11.5 g) dissolved in 20 mL of anhydrous tetrahydrofuran (THF) wasslowly added to a suspension of lithium aluminium hydride (4.10 g, 106mmol) in anhydrous THF (100 mL) at 0° C. The mixture was then warmed toroom temperature. After being stirred at room temperature for 1 hour,the reaction mixture was cooled to 0° C. and treated with water (4.1mL), followed by sodium hydroxide (10% aqueous solution, 4.1 mL). Theresulting slurry was filtered and washed with THF. The combined filtratewas evaporated to dryness and the residue was purified by silica gelcolumn chromatography to give(2,2-difluoro-benzo[1,3]dioxol-5-yl)-methanol (7.2 g, 76% over twosteps) as a colourless oil.

Step c: 5-Chloromethyl-2,2-difluoro-benzo[1,3]dioxole

Thionyl chloride (45 g, 38 mmol) was slowly added to a solution of(2,2-difluoro-benzo[1,3]dioxol-5-yl)-methanol (7.2 g, 38 mmol) indichloromethane (200 mL) at 0° C. The resulting mixture was stirredovernight at room temperature and then evaporated to dryness. Theresidue was partitioned between an aqueous solution of saturated sodiumbicarbonate (100 mL) and dichloromethane (100 mL). The separated aqueouslayer was extracted with dichloromethane (150 mL) and the organic layerwas dried over sodium sulfate, filtered, and evaporated to dryness togive crude 5-chloromethyl-2,2-difluoro-benzo[1,3]dioxole (4.4 g) whichwas used directly in the next step.

Step d: (2,2-Difluoro-benzo[1,3]dioxol-5-yl)-acetonitrile

A mixture of crude 5-chloromethyl-2,2-difluoro-benzo[1,3]dioxole (4.4 g)and sodium cyanide (1.36 g, 27.8 mmol) in dimethylsulfoxide (50 mL) wasstirred at room temperature overnight. The reaction mixture was pouredinto ice and extracted with ethyl acetate (300 mL). The organic layerwas dried over sodium sulfate and evaporated to dryness to give crude(2,2-difluoro-benzo[1,3]dioxol-5-yl)-acetonitrile (3.3 g) which was useddirectly in the next step.

Step e: 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile

Sodium hydroxide (50% aqueous solution, 10 mL) was slowly added to amixture of crude (2,2-difluoro-benzo[1,3]dioxol-5-yl)-acetonitrile,benzyltriethylammonium chloride (3.00 g, 15.3 mmol), and1-bromo-2-chloroethane (4.9 g, 38 mmol) at 70° C. The mixture wasstirred overnight at 70° C. before the reaction mixture was diluted withwater (30 mL) and extracted with ethyl acetate. The combined organiclayers were dried over sodium sulfate and evaporated to dryness to givecrude 1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile,which was used directly in the next step.

Step f 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylicacid

1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile (crudefrom the last step) was refluxed in 10% aqueous sodium hydroxide (50 mL)for 2.5 hours. The cooled reaction mixture was washed with ether (100mL) and the aqueous phase was acidified to pH 2 with 2M hydrochloricacid. The precipitated solid was filtered to give1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid as awhite solid (0.15 g, 1.6% over four steps). ESI-MS m/z calc. 242.2,found 243.3 (M+1)⁺; ¹H NMR (CDC₃) δ 7.14-7.04 (m, 2H), 6.98-6.96 (m,1H), 1.74-1.64 (m, 2H), 1.26-1.08 (m, 2H).

B. 1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid

A mixture of benzo[1,3]dioxole-5-acetonitrile (5.10 g, 31.7 mmol),1-bromo-2-chloro-ethane (9.0 mL, 109 mmol), and benzyltriethylammoniumchloride (0.181 g, 0.795 mmol) was heated at 70° C. and then 50%(wt./wt.) aqueous sodium hydroxide (26 mL) was slowly added to themixture. The reaction was stirred at 70° C. for 18 hours and then heatedat 130° C. for 24 hours. The dark brown reaction mixture was dilutedwith water (400 mL) and extracted once with an equal volume of ethylacetate and once with an equal volume of dichloromethane. The basicaqueous solution was acidified with concentrated hydrochloric acid to pHless than one and the precipitate filtered and washed with 1 Mhydrochloric acid. The solid material was dissolved in dichloromethane(400 mL) and extracted twice with equal volumes of 1 M hydrochloric acidand once with a saturated aqueous solution of sodium chloride. Theorganic solution was dried over sodium sulfate and evaporated to drynessto give a white to slightly off-white solid (5.23 g, 80%) ESI-MS m/zcalc. 206.1, found 207.1 (M+1)⁺. Retention time of 2.37 minutes. ¹H NMR(400 MHz, DMSO-d₆) δ 1.07-1.11 (m, 2H), 1.38-1.42 (m, 2H), 5.98 (s, 2H),6.79 (m, 2H), 6.88 (m, 1H), 12.26 (s, 1H).

C. 1-(2,3-Dihydrobenzofuran-5-yl)cyclopropanecarboxylic acid

Step a: 1-(4-Hydroxy-phenyl)-cyclopropanecarboxylic acid methyl ester

To a solution of methyl 1-(4-methoxyphenyl)cyclopropanecarboxylate (10.0g, 48.5 mmol) in dichloromethane (80 mL) was added EtSH (16 mL) underice-water bath. The mixture was stirred at 0° C. for 20 min before AlCl₃(19.5 g, 0.150 mmol) was added slowly at 0° C. The mixture was stirredat 0° C. for 30 min. The reaction mixture was poured into ice-water, theorganic layer was separated, and the aqueous phase was extracted withdichloromethane (50 mL x 3). The combined organic layers were washedwith H₂O, brine, dried over Na₂SO₄ and evaporated under vacuum to give1-(4-hydroxy-phenyl)-cyclopropanecarboxylic acid methyl ester (8.9 g,95%). ¹H NMR (400 MHz, CDC₃) δ 7.20-7.17 (m, 2H), 6.75-6.72 (m, 2H),5.56 (s, 1H), 3.63 (s, 3H), 1.60-1.57 (m, 2H), 1.17-1.15 (m, 2H).

Step b: 1-[4-(2,2-Diethoxy-ethoxy)-phenyl]-cyclopropanecarboxylic acid

To a stirred solution of 1-(4-hydroxy-phenyl)-cyclopropanecarboxylicacid methyl ester (15.0 g, 84.3 mmol) in DMF (50 mL) was added sodiumhydride (6.7 g, 170 mmol, 60% in mineral oil) at 0° C. After hydrogenevolution ceased, 2-bromo-1,1-diethoxy-ethane (16.5 g, 84.3 mmol) wasadded drop-wise to the reaction mixture. The reaction was stirred at160° C. for 15 hours. The reaction mixture was poured onto ice (100 g)and extracted with dichloromethane. The combined organics were driedover Na₂SO₄. The solvent was evaporated under vacuum to give crude1-[4-(2,2-diethoxy-ethoxy)-phenyl]-cyclopropanecarboxylic acid (10 g),which was used directly in the next step without purification.

Step c: 1-Benzofuran-5-yl-cyclopropanecarboxylic acid

To a suspension of crude1-[4-(2,2-diethoxy-ethoxy)-phenyl]-cyclopropanecarboxylic acid (20 g,−65 mmol) in xylene (100 mL) was added PPA (22.2 g, 64.9 mmol) at roomtemperature. The mixture was heated at reflux (140° C.) for 1 hourbefore it was cooled to room temperature and decanted from the PPA. Thesolvent was evaporated under vacuum to obtain the crude product, whichwas purified by preparative HPLC to provide1-(benzofuran-5-yl)cyclopropanecarboxylic acid (1.5 g, 5%). ¹H NMR (400MHz, DMSO-d₆) δ 12.25 (br s, 1H), 7.95 (d, J=2.8 Hz, 1H), 7.56 (d, J=2.0Hz, 1H), 7.47 (d, J=11.6 Hz, 1H), 7.25 (dd, J=2.4, 11.2 Hz, 1H), 6.89(d, J=1.6 Hz, 1H), 1.47-1.44 (m, 2H), 1.17-1.14 (m, 2H).

Step d: 1-(2,3-Dihydrobenzofuran-5-yl)cyclopropanecarboxylic acid

To a solution of 1-(benzofuran-5-yl)cyclopropanecarboxylic acid (700 mg,3.47 mmol) in MeOH (10 mL) was added PtO₂ (140 mg, 20%) at roomtemperature. The stirred reaction mixture was hydrogenated underhydrogen (1 atm) at 10° C. for 3 days. The reaction mixture wasfiltered. The solvent was evaporated under vacuum to afford the crudeproduct, which was purified by preparative HPLC to give1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxylic acid (330 mg, 47%).¹H NMR (400 MHz, CDC₃) δ 7.20 (s, 1H), 7.10 (d, J=10.8Hz, 1H), 6.73 (d,J=11.2Hz, 1H), 4.57 (t, J=11.6Hz, 2H), 3.20 (t, J=11.6 Hz, 2H),1.67-1.63 (m, 2H), 1.25-1.21 (m, 2H).

D. 1-(2,3-Dihydro-1H-inden-5-yl)cyclopropanecarboxylic acid

Step a: 1-(2,3-Dihydro-1H-inden-6-yl)ethanone

A mixture of 2,3-dihydro-1H-indene (100.0 g, 0.85 mol) and aceticanhydride (104.2 g, 1.35 mol) was added drop-wise to a slurry of AlCl₃(272.0 g, 2.04 mol) in CH₂Cl₂ (1000 ml) at 0° C. over a period of 3 h.The reaction mixture was stirred at room temperature under a nitrogenatmosphere for 15 h. Then the reaction mixture was poured into ice water(500 mL) and extracted with ethyl acetate (500 mL×3). The combinedorganic layers were washed with brine (500 mL), dried over Na₂SO₄ andevaporated in vacuo. The residue that was purified by columnchromatography (petroleum ether: ethyl acetate=20:1) to give the product(120.0 g, 88%). ¹H NMR (400 MHz, CDC₃) δ 2.08-2.15 (m, 2H), 2.58 (s,3H), 2.95 (t, J=7.2, 4 H), 7.28 (d, J=8.0, 1H), 7.75 (d, J=8.0, 1H) 7.82(s, 1H).

Step b: 2,3-dihydro-JH-indene-5-carboxylic acid

To a stirred aqueous sodium hypochlorite solution (2230 ml, 1.80 mmol,6□) at 55□ was added 1-(2,3-dihydro-1H-inden-6-yl) ethanone (120.0 g,0.75 mol) and the mixture was stirred at 55□ for 2 h. After cooling toroom temperature, saturated NaHCO₃ solution was added until the solutionbecame clear. The produced precipitate was filtered, washed severaltimes with water and dried to afford the desired product (120.0 g, 99%).¹H NMR (CDC₃, 300 MHz) δ 2.07-2.17 (m, 2H), 2.96 (t, J=7.5 Hz, 4H), 7.30(d, J=7.8, 1H,), 7.91 (d, J=7.8, 1H), 7.96 (s, 1H).

Step c: (2,3-dihydro-1H-inden-5-yl)methanol

To a stirred solution of lithium aluminium hydride (72.8 g, 1.92 mol) inTHF (2.5 L) at 0□ was slowly added 2,3-dihydro-1H-indene-5-carboxylicacid (100.0 g, 0.62 mol). The reaction mixture was stirred at 0□ for 1h. Then the reaction was quenched with H₂O (72 ml) and NaOH (68 ml,20%). The mixture was filtered and the organic layer was dried overNa₂SO₄, evaporated in vacuo and the residue was purified by columnchromatography (petroleum ether: ethyl acetate=10:1) to give the desiredproduct (82.0 g, 90%). ¹H NMR (CDC₃, 300 MHz); δ 2.03-2.13 (m, 2H), 2.91(t, J=7.5 Hz, 4H), 4.64 (s, 2H), 7.13 (d, J=7.5, 1H), 7.18-7.24 (m, 2H).

Step d: 5-(chloromethyl)-2,3-dihydro-1H-indene

Thionyl chloride (120 ml, 1.65 mol) was added drop-wise to a rapidlystirred mixture of (2,3-dihydro-1H-inden-5-yl)methanol (81.4 g, 0.55mol) in chloroform (500 ml) at 0° C. After the addition was complete,the resulting mixture was allowed to warm to room temperature and thestirring was continued for an additional 12 h. The chloroform wasevaporated under reduced pressure to give a residue, that was purifiedby column chromatography (petroleum ether: ethyl acetate=15:1) to afford5-(chloromethyl)-2,3-dihydro-1H-indene (90.5 g, 99%). ¹H NMR (300 MHz,CDC3) δ 2.06-2.19 (m, 4H), 2.93 (t, J=7.5, 4H), 4.54 (s, 2H), 7.15-7.31(m, 3H).

Step e: 2-(2,3-dihydro-1H-inden-5-yl)acetonitrile

To a stirred solution of 5-(chloromethyl)-2,3-dihydro-1H-indene (90.0 g,0.54 mol) in DMSO (500 ml) was added sodium cyanide (54.0 g, 1.08 mol)at 0° C. portion wise. The reaction mixture was then stirred at roomtemperature for 3 hours. The reaction was quenched with water (1000 ml),extracted with ethyl acetate (3×250 mL). The combined organic layerswere washed with brine, dried over Na₂SO₄ and evaporated in vacuo toafford 2-(2,3-dihydro-1H-inden-5-yl)acetonitrile (82.2 g, 97%), that wasused in the next step without further purification.

Step f 1-(2,3-dihydro-1H-inden-6-yl)cyclopropanecarbonitrile

To a stirred solution of 2-(2,3-dihydro-1H-inden-5-yl)acetonitrile (50.0g, 0.32 mol) in toluene (150 mL) was added sodium hydroxide (300 mL, 50percent in water W/W), 1-bromo-2-chloroethane (92.6 ml, 1.12 mol) and(n-Bu)₄NBr (5 g, 15.51 mmol). The mixture was heated at 60° C.overnight. After cooling to room temperature, the reaction mixture wasdiluted with water (400 mL) and extracted with EtOAc (3×200 mL). Thecombined organic extracts were washed with brine, dried over Na₂SO₄,filtered and concentrated under vacuum and purified by columnchromatography (petroleum ether: ethyl acetate=10:1) to yield1-(2,3-dihydro-1H-inden-6-yl)cyclopropanecarbonitrile (9.3 g, 16%). ¹HNMR (CDC₃, 300 MHz) δ 1.35-1.38 (m, 2H), 1.66-1.69 (m, 2H), 2.05-2.13(m, 2H), 2.87-294 (m, 4H), 7.07-7.22 (m, 3H).

Step g: 1-(2,3-dihydro-1H-inden-6-yl)cyclopropanecarboxylic acid

To a stirred 1-(2,3-dihydro-1H-inden-6-yl)cyclopropanecarbonitrile (9.3g, 50.8 mmol) in methanol (40 mL) was added a solution of 150 mL ofsodium hydroxide (25% NaOH w/w in water). The mixture was heated at 100°C. for 8 hours. After cooling to room temperature, the reaction mixturewas poured over ice-water (0° C.), the pH was adjusted to pH=4 withhydrogen chloride (1 N) and the mixture was extracted withdichloromethane (3×100 mL). The combined organic layers were dried overNa₂SO₄ and evaporated under vacuum. The residue that was purified bycolumn chromatography (petroleum ether: ethyl acetate=5:1) to give1-(2,3-dihydro-1H-inden-6-yl)cyclopropanecarboxylic acid (4.8 g, 47%).¹H NMR (CDC₃, 400 MHz) δ 1.23-1.26 (m, 2H), 1.62-1.65 (m, 2H), 2.03-210(m, 2H), 2.81-2.91 (m, 4H), 7.11-7.21 (m, 3H).

E. 2-(3-Chloro-4-methoxyphenyl)acetonitrile

To a suspension of t-BuOK (4.8 g, 40 mmol) in THF (30 mL) was added asolution of TosMIC (3.9 g, 20 mmol) in THF (10 mL) at −78° C. and themixture was stirred for 10 minutes. A solution of3-chloro-4-methoxy-benzaldehyde (1.7 g, 10 mmol) in THF (10 mL) wasadded dropwise, and the reaction was stirred at −78° C. for 1.5 hours.To the cooled reaction mixture was added methanol (10 mL) and themixture was heated at reflux for 30 minutes. The solvent were evaporatedto give a crude residue that was dissolved in water (20 mL). The aqueousphase was extracted with ethyl acetate (20 mL×3). The combined organiclayers were dried and evaporated under reduced pressure to give a crudeproduct that was purified by column chromatography (petroleumether/ethyl acetate 10:1) to yield2-(3-chloro-4-methoxyphenyl)acetonitrile (1.5 g, 83%). ¹H NMR (400 MHz,CDC₃) δ 7.33 (d, J=2.4 Hz, 1H), 7.20 (dd, J=2.4, 8.4 Hz, 1H), 6.92 (d,J=8.4 Hz, 1H), 3.91 (s, 3H), 3.68 (s, 2H). ¹³C NMR (100 MHz, CDC₃) δ154.8, 129.8, 127.3, 123.0, 122.7, 117.60, 112.4, 56.2, 22.4.

F. 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)acetonitrile

Step a: 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid ethyl ester

To a suspension of Cs₂CO₃ (270 g, 1.49 mol) in DMF (1000 mL) were added3,4-dihydroxybenzoic acid ethyl ester (54.6 g, 0.3 mol) and1,2-dibromoethane (54.3 g, 0.29 mol) at room temperature. The resultingmixture was stirred at 80° C. overnight and then poured into ice-water.The mixture was extracted with ethyl acetate (200 mL×3). The combinedorganic layers were washed with water (200 mL×3) and brine (100 mL),dried over Na₂SO₄ and concentrated to dryness. The residue was purifiedby column chromatography (petroleum ether/ethyl acetate 50:1) on silicagel to obtain 2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid ethylester (18 g, 29%). ¹H NMR (300 MHz, CDC₃) δ 7.53 (dd, J=1.8, 7.2 Hz,2H), 6.84-6.87 (m, 1H), 4.22-4.34 (m, 6H), 1.35 (t, J=7.2 Hz, 3H).

Step b: (2,3-Dihydro-benzo[1,4]dioxin-6-yl)-methanol

To a suspension of LiAlH₄ (2.8 g, 74 mmol) in THF (20 mL) was addeddropwise a solution of 2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acidethyl ester (15 g, 72 mmol) in THF (10 mL) at 0° C. under N₂ atmosphere.The mixture was stirred at room temperature for 1 h and then quenchedcarefully by addition of water (2.8 mL) and NaOH (10%, 28 mL) withcooling. The precipitated solid was filtered off and the filtrate wasevaporated to dryness to yield(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanol (10.6 g) that was takeninto the next step without further purification. ¹H NMR (300 MHz,DMSO-d₆) δ 6.73-6.78 (m, 3H), 5.02 (t, J=5.7 Hz, 1H), 4.34 (d, J=6.0 Hz,2H), 4.17-4.20 (m, 4H).

Step c: 6-Chloromethyl-2,3-dihydro-benzo[1,4]dioxine

A mixture of (2,3-dihydro-benzo[1,4]dioxin-6-yl)methanol (10.6 g) inSOCl₂ (10 mL) was stirred at room temperature for 10 min and then pouredinto ice-water. The organic layer was separated and the aqueous phasewas extracted with dichloromethane (50 mL x 3). The combined organiclayers were washed with saturated solution of NaHCO₃, water and brine,dried over Na₂SO₄ and concentrated to dryness to obtain6-chloromethyl-2,3-dihydro-benzo[1,4]dioxine (12 g, 88% over two steps),which was used directly in next step without further purification.

Step d: 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)acetonitrile

A mixture of 6-chloromethyl-2,3-dihydro-benzo[1,4]dioxine (12.5 g, 67.7mmol) and NaCN (4.30 g, 87.8 mmol) in DMSO (50 mL) was stirred at 25° C.for 1 h. The mixture was poured into water (150 mL) and then extractedwith dichloromethane (50 mL×4). The combined organic layers were washedwith water (50 mL×2), brine (50 mL), dried over Na₂SO₄ and concentratedto dryness. The residue was purified by silica gel column chromatography(petroleum ether/ethyl acetate 50:1) to yield2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetonitrile as a yellow oil(10.2 g, 86%). ¹H-NMR (300 MHz, CDCl₃) δ 6.78-6.86 (m, 3H), 4.25 (s,4H), 3.63 (s, 2H).

G. 2-(2,3-Dihydrobenzofuran-6-yl)acetonitrile

Step a: 6-(tert-Butyldimethylsilyloxy)benzofuran-3(2H)-one

To a solution of 6-hydroxybenzofuran-3(2H)-one (30.0 g, 200 mmol) indichloromethane (500 mL) was added TBSCl (36.0 g, 240 mmol) andimidazole (16.3 g, 240 mmol) at room temperature. The reaction mixturewas stirred at room temperature for 3 h. The solvent was removed underreduced pressure to afford6-(tert-butyldimethylsilyloxy)benzofuran-3(2H)-one (40.0 g, 80% yield),that was used directly in the next step without further purification.

Step b: Benzofuran-6-ol

NaBH₄ (6.0 g, 160 mmol) was added to a solution of6-(tert-butyldimethylsilyloxy)benzofuran-3(2H)-one (40.0 g, 151 mmol) inMeOH (800 mL) at room temperature. After stirring at room temperaturefor 2 h, the reaction mixture was treated with acetone. Subsequently 4NHCl were added to the mixture and the stirring was continued for 3 h atroom temperature. The mixture was diluted with water and extracted withethyl acetate (3×1000 mL). The extract was washed with brine, dried,concentrated in vacuo and purified by column chromatography on silicagel (5-10% ethyl acetate in petroleum ether) to afford the pure product(17.0 g, 85.5% yield). ¹H NMR (300 MHz, CDC₃) δ: 7.51 (d, J=2.1, 1H),7.41 (d, J=8.4, 1H), 7.02 (d, J=1.8, 1H), 6.81 (dd, J=8.4, 2.1, 1H),6.68 (dd, J=2.1, 0.9, 1H), 5.5 (br s, 1H).

Step c: Benzofuran-6-yl trifluoromethanesulfonate

To a stirred solution of benzofuran-6-ol (17.0 g, 127 mmol) in pyridine(20 g, 254 mmol) and dichloromethane (200 mL) was added Tf₂O (53.7 g,190 mmol). The reaction mixture was stirred at room temperature for 16h. The reaction mixture was diluted with water, and extracted with ethylacetate. The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated to afford a crude product that waspurified by column chromatography on silica gel (5-10% ethyl acetate inpetroleum ether) to afford benzofuran-6-yl trifluoromethanesulfonate(30.0 g, 88.0% yield). ¹H NMR (300 MHz, CDC₃) δ: 7.72 (d, J=2.1, 1H),7.67 (d, J=8.7, 1H), 7.48 (d, J=1.5, 1H), 7.19 (dd, J=8.7, 2.1, 1H),6.82-6.91 (m, 1H).

Step d: Methyl benzofuran-6-carboxylate

A mixture of benzofuran-6-yl trifluoromethanesulfonate (16.2 g, 61mmol), 1,3-bis(diphenyl phosphino)propane (1.4 g, 3.3 mmol) and Pd(OAc)₂(756 mg, 3.3 mmol) in DIEA (16.2 g, 124 mmol), MeOH (153 mL) and DMF(153 mL) was stirred at 70□ under atmosphere of CO for 24 h. Thereaction mixture was diluted with water, and extracted with ethylacetate. The combined organic layer was then washed with brine and driedover Na₂SO₄, filtered and concentrated to afford a crude mixture thatwas purified by column chromatography on silica gel (5-10% ethyl acetatein petroleum ether) to yield methyl benzofuran-6-carboxylate (8.5 g, 80%yield). ¹H NMR (300 MHz, CDC₃) δ: 8.21 (s, 1H), 7.96 (dd, J=8.1, 1.5,1H), 7.76 (d, J=2.1, 1H), 7.63 (d, J=8.1, 1H), 6.83-6.82 (m, 1H), 3.95(s, 1H).

Step e: Methyl 2,3-dihydrobenzofuran-6-carboxylate

A mixture of methyl benzofuran-6-carboxylate (17.8 g, 100 mmol) and 10%Pd/C (10.5 g) in MeOH was stirred under hydrogen atmosphere at 50 psifor 2 h. The catalyst was removed by filtration. The solvent was removedunder reduced pressure to afford the desired methyl2,3-dihydrobenzofuran-6-carboxylate (17.8 g, 98.5% yield). ¹H NMR (400MHz, CDC₃) δ: 7.57 (d, J=7.6, 1H), 7.40 (s, 1H), 7.23 (d, J=7.6, 1H),4.61 (t, J=8.8, 2H), 3.89 (s, 3H), 3.25 (t, J=8.8, 2H).

Step f: (2,3-Dihydrobenzofuran-6-yl)methanol

To a stirred solution of lithium aluminium hydride (6.1 g, 250 mmol) inTHF (300 mL) was added a solution of methyl2,3-dihydrobenzofuran-6-carboxylate (17.8 g, 100 mmol) in THF at 0□. Themixture was stirred at room temperature for 1 h. A saturated aqueousNaOH solution was added and the mixture was extracted with ethylacetate. The combined organic layers were washed with brine and driedover Na₂SO₄, filtered and concentrated to afford(2,3-dihydrobenzofuran-6-yl)methanol (13.8 g, 92.0% yield). ¹H NMR (400MHz, CDC₃) δ: 7.17 (d, J=7.2, 1H), 6.84 (d, J=7.2, 1H), 6.81 (s, 1H),4.62 (s, 2H), 4.58 (t, J=8.4, 2H), 3.20 (t, J=8.4, 2H),) 1.67 (br s,1H).

Step g: 6-(Chloromethyl)-2,3-dihydrobenzofuran

To a solution of (2,3-dihydrobenzofuran-6-yl)methanol (13.8 g, 92 mmol)in CHCl₃ (200 mL) was slowly added SOCl₂ at 0□. The reaction mixture wasstirred at reflux for 4 h. After the solvent was removed, saturatedNaHCO₃ and ethyl acetate were added to the mixture. The organic layerwas extracted with ethyl acetate. The combined organic layer was thenwashed with brine and dried over Na₂SO₄, filtered and concentrated toafford 6-(chloromethyl)-2,3-dihydrobenzofuran (12.3 g, 80.0% yield). ¹HNMR (400 MHz, CDC₃) δ: 7.16 (d, J=7.5, 1H), 6.87 (d, J=7.5, 1H), 6.83(s, 1H), 4.58 (t, J=8.7, 2H), 4.49 (s, 2H), 3.20 (t, J=8.7, 2H).

Step h: 2-(2,3-Dihydrobenzofuran-6-yl)acetonitrile

To a solution of 6-(chloromethyl)-2,3-dihydrobenzofuran (12.3 g, 73mmol) in DMSO (100 mL) was added KCN (7.1 g, 109.5 mmol). The reactionmixture was stirred at 100□ for 2 hours. The mixture was diluted withwater and extracted with ethyl acetate (3×200 mL). The combined organiclayers were washed with brine, dried, concentrated in vacuo and purifiedby column chromatography on silica gel (5-10% ethyl acetate in petroleumether) to afford 2-(2,3-dihydrobenzofuran-6-yl)acetonitrile (8.4 g,70.4% yield). ¹H NMR (400 MHz, CDC₃) δ: 7.16 (d, J=7.6, 1H), 6.79 (d,J=7.2, 1H), 6.72 (s, 1H), 4.58 (t, J=8.4, 2H), 3.67 (s, 2H), 3.19 (t,J=8.4, 2H).

The following acids were commercially available or were prepared asdescribed above

Structure Name

1-(1,3-dihydroisobenzofuran-5- yl)cyclopropanecarboxylic acid

1-(2,3-dihydrobenzofuran-6- yl)cyclopropanecarboxylic acid

1-(2,3-dihydrobenzo[b][1,4]dioxin- 6-yl)cyclopropanecarboxylic acid

1-(3-methoxyphenyl)cyclopropane- carboxylic acid

1-(4-chlorophenyl)cyclopropane- carboxylic acid

1-(3-chloro-4- methoxyphenyl)cyclopropane- carboxylic acid

G. 6-Chloro-5-methylpyridin-2-amine

Step a: 2,2-Dimethyl-N-(5-methyl-pyridin-2-A-propionamide

To a stirred solution of 5-methylpyridin-2-amine (200 g, 1.85 mol) inanhydrous CH₂Cl₂ (1000 mL) was added drop wise a solution of Et₃N (513mL, 3.70 mol) and 2,2-dimethyl-propionyl chloride (274 mL, 2.22 mol) at0° C. under N₂. The ice bath was removed and stirring was continued atroom temperature for 2 hours. The reaction was poured into ice (2000 g).The organic layer was separated and the remaining aqueous layer wasextracted with CH₂Cl₂ (3×). The combined organics were dried over Na₂SO₄and evaporated to afford2,2-dimethyl-N-(5-methyl-pyridin-2-yl)-propionamide (350 g), which wasused in the next step without further purification. ¹H NMR (400 MHz,CDC₃) δ 8.12 (d, J=8.4 Hz, 1H), 8.06 (d, J=1.2 Hz, 1H), 7.96 (s, 1H),7.49 (dd, J=1.6, 8.4 Hz, 1H), 2.27 (s, 1H), 1.30 (s, 9H).

Step b: 2,2-Dimethyl-N-(5-methyl-1-oxy-pyridin-2-yl)-propionamide

To a stirred solution of2,2-dimethyl-N-(5-methyl-pyridin-2-yl)-propionamide (100 g, 0.52 mol) inAcOH (500 mL) was added drop-wise 30% H₂O₂ (80 mL, 2.6 mol) at roomtemperature. The mixture was stirred at 80° C. for 12 hours. Thereaction mixture was evaporated under vacuum to obtain2,2-dimethyl-N-(5-methyl-1-oxy-pyridin-2-yl)-propionamide (80 g, 85%purity). ¹H NMR (400 MHz, CDC₃) δ 10.26 (br s, 1H), 8.33 (d, J=8.4 Hz,1H), 8.12 (s, 1H), 7.17 (dd, J=0.8, 8.8 Hz, 1H), 2.28 (s, 1H), 1.34 (s,9H).

Step c: N-(6-Chloro-5-methyl-pyridin-2-yl)-2,2-dimethyl-propionamide

To a stirred solution of2,2-dimethyl-N-(5-methyl-1-oxy-pyridin-2-yl)-propionamide (10 g, 48mmol) in anhydrous CH₂Cl₂ (50 mL) was added Et₃N (60 mL, 240 mmol) atroom temperature. After being stirred for 30 min, POCl₃ (20 mL) wasadded drop-wise to the reaction mixture. The reaction was stirred at 50°C. for 15 hours. The reaction mixture was poured into ice (200 g). Theorganic layer was separated and the remaining aqueous layer wasextracted with CH₂Cl₂ (3×). The combined organics were dried overNa₂SO₄. The solvent was evaporated under vacuum to obtain the crudeproduct, which was purified by column chromatography (PetroleumEther/EtOAc 100:1) to provideN-(6-chloro-5-methyl-pyridin-2-yl)-2,2-dimethyl-propionamide (0.5 g,5%). ¹H NMR (400 MHz, CDC₃) δ 8.09 (d, J=8.0 Hz, 1H), 7.94 (br s, 1H),7.55 (d, J=8.4 Hz, 1H), 2.33 (s, 1H), 1.30 (s, 9H).

Step d: 6-Chloro-5-methyl-pyridin-2-ylamine

To N-(6-chloro-5-methyl-pyridin-2-yl)-2,2-dimethyl-propionamide (4.00 g,17.7 mmol) was added 6 N HCl (20 mL) at room temperature. The mixturewas stirred at 80° C. for 12 hours. The reaction mixture was basifiedwith drop-wise addition of sat. NaHCO₃ to pH 8-9, and then the mixturewas extracted with CH₂Cl₂ (3×). The organic phases were dried overNa₂SO₄ and evaporated under vacuum to obtain the6-chloro-5-methyl-pyridin-2-ylamine (900 mg, 36%). ¹H NMR (400 MHz,CDC₃) δ 7.28 (d, J=8.0 Hz, 1H), 6.35 (d, J=8.0 Hz, 1H), 4.39 (br s, 2H),2.22 (s, 3H). MS (ESI) m/z: 143 (M+H+).

H. 6-Chloro-5-ethylpyridin-2-amine

Step a: N-(5-Bromopyridin-2-yl)pivalamide

Pivaloyl chloride (85 mL, 0.69 mol) was added to a solution of5-bromopyridin-2-amine (100 g, 0.58 mol) and Et₃N (120 mL, 0.87 mmoL) inCH₂Cl₂ at −78° C. The temperature was allowed to warm to roomtemperature and the stirring was continued overnight. The reactionmixture was poured into water, extracted with CH₂Cl₂, dried over MgSO₄,evaporated in vacuo and purified by silica gel column chromatography(10% EtOAc in petroleum ether) to affordN-(5-bromopyridin-2-yl)pivalamide (130 g, 87% yield). ¹H NMR (CDC₃, 400MHz) δ 8.28 (d, J=2.0 Hz, 1H), 8.17 (d, J=9.2 Hz, 1H), 7.99 (br s, 1H),7.77 (dd, J=9.2 and 2.0, 1H), 1.28 (s, 9H).

Step b: N-(5-Vinylpyridin-2-yl)pivalamide

Tributyl(vinyl)stannane (50 g, 0.16 mol), Pd(Ph₃P)₄ (3.3 g, 2.9 mmol)and a catalytic amount of 2,6-t-butyl-4-methylphenol was added to asolution of N-(5-bromopyridin-2-yl)pivalamide (36 g, 0.14 mol) intoluene. The reaction mixture was heated at reflux for 48 h. The solventwas evaporated in vacuo and the residue was purified by chromatographyon silica gel (5% EtOAc in petroleum ether) to affordN-(5-vinylpyridin-2-yl)pivalamide (23 g, 80% yield). ¹H NMR (CDC₃, 300MHz) δ 8.24-8.20 (m, 2H), 8.02 (br s, 1H), 7.77 (dd, J=8.7 and 2.4, 1H),6.65 (dd, J=17.7 and 10.8, 1H), 5.73 (d, J=17.7, 1H), 5.29 (d, J=10.8,1H), 1.32 (s, 9H).

Step c: N-(5-Ethylpyridin-2-yl)pivalamide

A catalytic amount of Pd/C was added to a solution ofN-(5-vinylpyridin-2-yl)pivalamide (23 g, 0.11 mol) in EtOH (200 mL). Thereaction mixture was stirred under hydrogen atmosphere overnight. Thecatalyst was filtrated off and the solution was concentrated in vacuo toafford N-(5-ethylpyridin-2-yl)pivalamide (22 g, 95%). ¹H NMR (CDC₃, 300MHz) δ 8.15 (d, J=8.4, 1H), 8.09 (d, J=2.4, 1H), 7.96 (br s, 1H), 7.54(dd, J=8.4 and 2.4, 1H), 2.61 (q, J=7.5, 2H), 1.30 (s, 9H), 1.23 (t,J=7.5, 3H).

Step d: 5-Ethyl-2-pivalamidopyridine 1-oxide

H₂O₂ (30%, 34 mL, 0.33 mol) was added to a solution ofN-(5-ethylpyridin-2-yl)pivalamide (22 g, 0.11 mol) in acetic acid (200mL). The mixture was stirred overnight at 80° C. The reaction mixturewas poured into water and was extracted with EtOAc. The organics werewashed with saturated Na₂SO₃ solution and NaHCO₃ solution before beingdried over MgSO₄. The solvent was evaporated in vacuo to afford5-ethyl-2-pivalamidopyridine 1-oxide (16 g, 67%), which was used for thenext step without further purification.

Step e: N-(6-Chloro-5-ethylpyridin-2-yl)pivalamide

Et₃N (123 mL, 93.6 mmol) was added to a solution of5-ethyl-2-pivalamidopyridine 1-oxide (16.0 g, 72.0 mmol) in POC₃ (250mL) and the reaction mixture was heated at reflux for 3 days. ExcessPOC₃ was distilled off and the residue was poured into water. Themixture was neutralized with aqueous NaOH to pH 9. The aqueous layer wasextracted with ethyl acetate. The organic layer was dried over MgSO₄ andthe solvent was evaporated in vacuo. The residue was purified bychromatography on silica gel (10% EtOAc in petroleum ether) to affordN-(6-chloro-5-ethylpyridin-2-yl)pivalamide (900 mg, 5%) and unreacted5-ethyl-2-pivalamidopyridine 1-oxide (4.8 g). ¹H NMR (CDC₃, 300 MHz) δ8.12 (d, J=8.7, 1H), 7.94 (br s, 1H), 7.56 (d, J=8.7, 1H), 2.70 (q,J=7.5, 2H), 1.30 (s, 9H), 1.23 (t, J=7.5, 3H).

Step f: 6-Chloro-5-ethylpyridin-2-amine

A suspension of N-(6-chloro-5-ethylpyridin-2-yl)pivalamide (1.16 g, 4.82mmol) in 6N HCl (20 mL) was heated at reflux overnight. The reactionmixture was cooled to room temperature and was treated with aqueous NaOHto pH 8. The aqueous layer was extracted with EtOAc. The organic layerwas dried over MgSO₄ and the solvent was evaporated in vacuo. Theresidue was purified by chromatography on silica gel (5% EtOAc inpetroleum ether) to afford 6-chloro-5-ethylpyridin-2-amine (650 mg,86%). ¹H NMR (CDC₃, 400 MHz) δ 7.35 (d, J=8.4, 1H), 6.45 (d, J=8.4, 1H),2.61 (q, J=7.6, 2H), 1.18 (t, J=7.6, 3H).

I. 6-Bromo-5-chloropyridin-2-amine

Step a: N-(6-Bromopyridin-2-yl)acetamide

To a solution of 6-bromopyridin-2-amine (10 g, 0.060 mol) and Et₃N (25g, 0.27 mol) in CH₂Cl₂ (300 mL) was added AcCl (13 g, 0.17 mol) at 0° C.The mixture was stirred overnight. The reaction mixture was diluted withwater and extracted with EtOAc (200 mL x 3). The combined organic layerswere dried over anhydrous Na₂SO₄ and evaporated under vacuum to giveN-(6-bromopyridin-2-yl)acetamide (11 g, 88%). ¹H NMR (400 MHz, CDC₃) δ8.15 (d, J=8.0 Hz, 1H), 7.97 (brs, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.18 (d,J=8.0 Hz, 1H), 2.19 (s, 3H).

Step b: 6-Bromo-5-nitropyridin-2-amine

To a solution of N-(6-bromopyridin-2-yl)acetamide (9.0 g, 40 mmol) inH₂SO₄ (100 mL) was added HNO₃ (69%, 5.5 g, 60 mmol) dropwise at 0° C.The mixture was stirred at this temperature for 4 hours, and was thenpoured into ice-water. The mixture was extracted with EtOAc (100 mL x3). The combined organic layers were dried over anhydrous Na₂SO₄ andevaporated under vacuum to give 6-bromo-5-nitropyridin-2-amine (7.5 g,82%). ¹H NMR (400 MHz, DMSO) δ 8.10 (d, J=8.8 Hz, 1H), 7.73 (brs, 2H),6.46 (d, J=8.8 Hz, 1H).

Step c: Methyl 6-bromo-5-nitropyridin-2-ylcarbamate

To a solution of 6-bromo-5-nitropyridin-2-amine (1.4 g, 10 mmol), Et₃N(2.0 g, 20 mol) and DMAP (70 mg) in CH₂Cl₂ (20 mL) was added C1CO₂Me(1.3 g, 10 mmol) drop-wise at 0° C. The mixture was stirred overnight.The reaction mixture was diluted with water and extracted with EtOAc (20mL x 3). The combined organic layers were dried over anhydrous Na₂SO₄and evaporated under vacuum to give methyl6-bromo-5-nitropyridin-2-ylcarbamate (1.4 g, 82%). ¹H NMR (400 MHz,DMSO) δ 10.78 (brs, 1H), 8.56 (d, J=9.2 Hz, 1H), 8.05 (d, J=8.4 Hz, 1H),3.70 (s, 3H).

Step d: Methyl 5-amino-6-bromopyridin-2-ylcarbamate

To a solution of methyl 6-bromo-5-nitropyridin-2-ylcarbamate (700 mg,2.5 mmol) in CH₃OH (20 mL) was added NiCl₂ (1.2 g, 5.1 mmol) and NaBH₄(300 mg, 7.6 mmol) successively at 0° C. The mixture was stirred for 20seconds. The reaction mixture was diluted with water and extracted withEtOAc (20 mL x 3). The combined organic layers were dried over anhydrousNa₂SO₄ and evaporated under vacuum to give methyl5-amino-6-bromopyridin-2-ylcarbamate (600 mg, 96%). ¹H NMR (400 MHz,CDC₃) 6.7.75 (d, J=8.4 Hz, 1H), 7.13 (brs, 1H), 7.09 (d, J=8.8 Hz, 1H),3.81 (s, 3H).

Step e: Methyl 6-bromo-5-chloropyridin-2-ylcarbamate

To a mixture of methyl 5-amino-6-bromopyridin-2-ylcarbamate (100 mg,0.41 mmol) and CuCl (120 mg, 1.6 mmol) in HCl (28%, 10 mL) was added andNaNO₂ (29 mg, 0.41 mmol) at 0° C. The mixture was stirred at roomtemperature for 2 hr. The reaction mixture was diluted with water andextracted with ethyl acetate (20 mL x 3). The combined organic layerswere dried over anhydrous Na₂SO₄ and evaporated under vacuum to givemethyl 6-bromo-5-chloropyridin-2-ylcarbamate (80 mg, 75%). ¹H NMR (400MHz, CDC₃) δ 7.93 (d, J=8.8 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.38 (brs,1H), 3.82 (s, 3H).

Step f: 6-Bromo-5-chloropyridin-2-amine

To a solution of methyl 6-bromo-5-chloropyridin-2-ylcarbamate (1.1 g,4.1 mmol) in methanol (50 mL) was added KOH (700 mg, 13 mmol) at roomtemperature. The mixture was heated at reflux for 2 hr. The reactionmixture was diluted with water and extracted with ethyl acetate (20mL×3). The combined organic layers were dried over anhydrous Na₂SO₄ andevaporated under vacuum. The residue was purified by columnchromatography on silica gel (5% to 10% EtOAc in petroleum ether) togive 6-bromo-5-chloropyridin-2-amine (700 mg, 81%). ¹H NMR (400 MHz,CDC₃) δ 7.54 (d, J=8.0 Hz, 1H), 6.41 (d, J=8.4 Hz, 1H).

J. 6-Chloro-4-methylpyridin-2-amine

Step a: N-(4-Methylpyridin-2-yl)pivalamide

To a solution of 4-methylpyridin-2-amine (25.0 g, 0.230 mol) and Et₃N(35.0 g, 0.350 mmol) in CH₂Cl₂ (200 ml) was added pivaloyl chloride(33.1 g, 0.270 mol) drop-wise. The mixture was stirred for 4 h under N₂atmosphere. The reaction mixture was quenched with water and wasextracted with ethyl acetate (200 mL x 3). The combined organic extractswere dried over anhydrous Na₂SO₄, evaporated under vacuum and purifiedby chromatography on silica gel (20% ethyl acetate in petroleum ether)to afford N-(4-methylpyridin-2-yl)pivalamide (36.2 g, 82%). ¹H NMR(CDC₃, 300 MHz) δ 8.09-8.08 (m, 2H), 8.00 (br s, 1H), 6.83 (dd, J=4.8,0.6 Hz, 1H), 2.33 (s, 3H), 1.30 (s, 9H).

Step b: 4-Methylpyridin-2-ylpivalamide-1-oxide

To a solution of N-(4-methylpyridin-2-yl)pivalamide (10 g, 52 mmol) inAcOH (300 ml) was added H₂O₂ (7.0 ml, 68 mmol) drop-wise at 0° C. Themixture was stirred overnight at 70° C. The reaction mixture wasquenched with water, extracted with ethyl acetate (200 mL×3) and washedwith saturated Na₂SO₃. The combined organic extracts were dried overanhydrous Na₂SO₄, and evaporated under vacuum. The residue was purifiedby chromatography on silica gel (5% ethyl acetate in petroleum ether) toafford 4-methylpyridin-2-ylpivalamide-1-oxide (8.4 g, 77%). ¹H NMR(CDC₃, 300 MHz) δ 10.38 (br s, 1H), 10.21 (br s, 1H), 8.34 (s, 1H), 8.26(d, J=6.9 Hz, 1H), 6.83 (d, J=6.9 Hz, 1H), 2.37 (s, 3H), 1.33 (s, 9H).

Step c: N-(6-Chloro-4-methylpyridin-2-yl)pivalamide

To a solution of 4-methylpyridin-2-yl-pivalamide-1-oxide (3.0 g, 14mmol) in POCl₃ (30 mL) was added Et₃N (6.0 mL, 43 mmol) drop-wise at 0°C. Then mixture was stirred at 100° C. for 3 days. The mixture wasquenched with water, treated with aqueous NaOH to pH 8-9, and extractedwith ethyl acetate (50 mL x 3). The combined organic extracts were driedover anhydrous Na₂SO₄, evaporated under vacuum and purified bychromatography on silica gel (15% ethyl acetate in petroleum ether) toafford N-(6-chloro-4-methylpyridin-2-yl)pivalamide (520 mg, 16%). ¹H NMR(CDC₃, 300 MHz) δ 8.03 (s, 1H), 7.93 (br s, 1H), 6.87 (s, 1H), 2.33 (s,3H), 1.29 (s, 9H).

Step d: 6-Chloro-4-methylpyridin-2-amine

A solution of N-(6-chloro-4-methylpyridin-2-yl)pivalamide (500 mg, 2.21mmol) in HCl (40 mL, 6 M) was stirred for 6 hours at 90° C. The mixturewas cooled to room temperature and neutralized with NaOH to pH 10. Themixture was extracted with ethyl acetate, evaporated under vacuum, andpurified by chromatography on silica gel (5% ethyl acetate in petroleumether) to afford 6-chloro-4-methylpyridin-2-amine (257 mg, 82%). ¹H NMR(CDC₃, 300 MHz) δ 6.52 (s, 1H), 6.26 (s, 1H), 2.23 (s, 3H).

K. 6-Chloro-4,5-dimethylpyridin-2-amine

Step a: 3,4-Dimethylpyridine 1-oxide

To a solution of 3,4-dimethylpyridine (100.0 g, 0.93 mol) indichloromethane was added m-CPBA (320.0 g, 1.87 mol) at the roomtemperature. The reaction mixture was stirred at room temperatureovernight, and then quenched with saturated solution of Na₂S₂O₃ (100mL). The organic layer was separated and the aqueous phase was extractedwith CH₂Cl₂ (300 mL x 3). The combined organic layers were dried overanhydrous Na₂SO₄, filtered and evaporated under vacuum to yield aresidue that was purified by column chromatography on silica gel(10-100% MeOH in EtOAc) to give 3,4-dimethylpyridine 1-oxide (70.0 g,61%).

Step b: 2,2-Dimethyl-2H-benzo[e][1,3]oxazin-4(3H)-one

To a solution of 3-hydroxy-benzamide (50 g, 0.36 mol) in acetone (300mL) was added 2,2-dimethoxy-propane (100 mL) and p-toluene sulfonic acid(5 g, 0.03 mol) and the mixture was heated to reflux overnight. Thesolvent was evaporated under vacuum to give crude2,2-dimethyl-2H-benzo[e][1,3]oxazin-4(3H)-one (55 g, 86%) that was usedin the next step without further purification. ¹H NMR (300 MHz, CDC₃) δ7.91 (dd, J=1.8, 7.8 Hz 1H), 7.44 (t, J=7.8 Hz 1H), 7.35 (brs, 1H), 7.05(t, J=7.8 Hz 1H), 6.91 (d, J=8.1 Hz 1H), 1.65 (s, 6H).

Step c: 4-Chloro-2,2-dimethyl-2H-benzo[e][1,3]oxazine

To a solution of 2,2-dimethyl-2H-benzo[e][1,3]oxazin-4(3H)-one (100 g,0.56 mol) in POCl₃ (500 mL) was added PCl₅ (170 g, 0.84 mol) at the roomtemperature. The mixture was hearted at 60° C. overnight. The solventwas removed by distillation under atmospheric pressure and the residuewas distilled under reduced pressure (85-86° C., 2.5 mmHg) to give4-chloro-2,2-dimethyl-2H-benzo[e][1,3]oxazine (50 g, 45%). ¹H NMR (400MHz, CDCl₃) δ 7.55 (dd, J=1.6, 8.4 Hz, 1H), 7.38 (dt, J=1.6, 8.0 Hz 1H),6.95 (t, J=6.8 Hz 1H), 6.79 (d, J=8.0 Hz 1H), 1.61 (s, 6H).

Step d:3-(4,5-dimethylpyridin-2-yl)-2,2-dimethyl-2H-benzo[e][1,3]oxazin-4(3H)-one

To a solution of 4-chloro-2,2-dimethyl-2H-benzo[e][1,3]oxazine (50 g,0.26 mol) in CH₂Cl₂ (200 mL) was added 33,4-dimethylpyridine 1-oxide (65g, 0.52 mol) at the room temperature. The mixture was heated to refluxovernight. The precipitate was filtered off and the filtrate wasconcentrated under vacuum to yield a residue that was purified by columnchromatography on silica gel (10% ethyl acetate in petroleum ether) togive3-(4,5-dimethylpyridin-2-yl)-2,2-dimethyl-2H-benzo[e][1,3]oxazin-4(3H)-one(9 g, 13%). ¹H NMR (300 MHz, d-DMSO) δ 8.25 (s, 1H), 7.78 (d, J=6.6 Hz,1H), 7.54-7.51 (m, 1H), 7.16-7.11 (m, 2H), 7.05 (d, J=8.4 Hz, 1H), 2.26(s, 3H), 2.23 (s, 3H), 1.60 (s, 6H)

Step e: 4,5-Dimethylpyridin-2-amine

A solution of3-(4,5-dimethylpyridin-2-yl)-2,2-dimethyl-2H-benzo[e][1,3]oxazin-4(3H)-one(9 g, 0.03 mol) in concentrated hydrochloric acid (100 mL) was heated atreflux overnight. The mixture was basified by saturated solution ofNa₂CO₃ and extracted with CH₂Cl₂ (100 mL×3). The combined organic layerswere dried over anhydrous Na₂SO₄, filtered and evaporated under vacuumto give 4,5-dimethylpyridin-2-amine (3.8 g, 97%), that was directly usedin the next step without further purification.

Step f: 2-(4,5-dimethylpyridin-2-yl)-isoindoline-1,3-dione

To a solution of 4,5-dimethylpyridin-2-amine (2.1 g, 0.02 mol) in aceticacid (40 mL) was added isobenzofuran-1,3-dione (2.5 g, 0.02 mol) at theroom temperature. The mixture was heated at 90° C. overnight. Theresulting solution was basified by saturated solution of NaHCO₃ andextracted with ethyl acetate (50 mL×3). The combined organic layers weredried over anhydrous Na₂SO₄, filtered and evaporated under vacuum togive 2-(4,5-dimethylpyridin-2-yl)-isoindoline-1,3-dione (1.7 g, 40%)¹HNMR (300 MHz, DMSO) δ 8.33 (s, 1H), 7.97-7.91 (m, 4H), 7.32 (s, 1H),2.30 (s, 3H), 2.27 (s, 3H).

Step g: 2-(1,3-Dioxoisoindolin-2-yl)-4,5-dimethylpyridine 1-oxide

To a solution of 2-(4,5-dimethylpyridin-2-yl)-isoindoline-1,3-dione (1.7g, 0.01 mol) in CH₂Cl₂ (50 mL) was added m-CPBA (3.5 g, 0.02 mol) at theroom temperature. The mixture was stirred overnight, then quenched byaddition of a saturated solution of Na₂S₂O₃ (100 mL). The organic layerwas separated and the aqueous phase was extracted with CH₂Cl₂ (50 mL×3).The combined organic layers were dried over anhydrous Na₂SO₄, filteredand evaporated under vacuum to give2-(1,3-dioxoisoindolin-2-yl)-4,5-dimethylpyridine 1-oxide (1.5 g, 83%),which was used directly in the next step.

Step h: 2-(6-chloro-4,5-dimethylpyridin-2-yl)isoindoline-1,3-dione

To a solution of 2-(1,3-dioxoisoindolin-2-yl)-4,5-dimethylpyridine1-oxide (1.5 g, 0.01 mol) in POCl₃ (50 mL) was added Et₃N (680 mg, 0.01mol) at room temperature. The mixture was stirred at 80□ for 2 hr, andthen carefully poured into the mixture of saturation NaHCO₃ solution andice water. The mixture was extracted with EtOAc (50 mL×3). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered and evaporatedunder vacuum to give a crude residue that was purified by columnchromatography on silica gel (10-15% ethyl acetate in petroleum ether)to give 2-(6-chloro-4,5-dimethylpyridin-2-yl)isoindoline-1,3-dione (650mg, 41%). ¹H NMR (300 MHz, CDC₃) δ 7.97-7.92 (m, 2H), 7.82-7.78 (m, 2H),7.16 (s, 1H), 2.41 (s, 3H), 2.39 (s, 3H).

Step i: 6-Chloro-4,5-dimethylpyridin-2-amine

A solution of 2-(6-chloro-4,5-dimethylpyridin-2-yl)isoindoline-1,3-dione(650 mg, 2.27 mmol) in ammonia in methanol (2 M, 50 mL) was stirred atthe room temperature overnight. The mixture was diluted with water (50mL) and extracted with ethyl acetate (50 mL×3). The combined organiclayers were dried over anhydrous Na₂SO₄, filtered and evaporated undervacuum to give a crude residue that was purified by silica gel columnchromatography (10-15% ethyl acetate in petroleum ether) to give6-chloro-4,5-dimethylpyridin-2-amine (160 mg, 46%). ¹H NMR (300 MHz,d-DMSO) δ 6.21 (s, 1H), 5.93 (brs, 2H), 2.11 (s, 3H), 2.05 (s, 3H). MS(ESI) m/z (M+H⁺): 157.2.

L.N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide

Step a: 1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonylchloride

To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid(18.8 g, 78.0 mmol) in thionyl chloride (17.0 mL, 233 mmol) was addedN,N-dimethylformamide (200 μL, 2.6 mmol). The reaction mixture wasstirred at room temperature for 2 hours. Excess thionyl chloride andN,N-dimethylformamide were removed in vacuo and the resulting acidchloride was used directly in next step.

Step b:N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide

To a solution of 6-chloro-5-methylpyridin-2-amine (11.1 g, 78.0 mmol)and Et₃N (22.0 mL, 156 mmol) in dichloromethane (100 mL) was added asolution of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonylchloride (20.3 g, 78.0 mmol) in dichloromethane (50 mL). The resultingreaction mixture was allowed to stir at room temperature for 18 hours.The reaction mixture was then washed with 1N aqueous NaOH (2×200 mL), 1N aqueous HCl (1×200 mL), and saturated aqueous NaHCO₃ (1×200 mL). Theorganics were dried over sodium sulfate and evaporated to yieldN-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(26.9 g, 94% over two steps). ESI-MS m/z calc. 366.1, found 367.3(M+1)⁺. Retention time 2.19 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 9.30(s, 1H), 7.89-7.87 (m, 1H), 7.78-7.76 (m, 1H), 7.54-7.53 (m, 1H),7.41-7.39 (m, 1H), 7.33-7.30 (m, 1H), 2.26 (s, 3H), 1.52-1.49 (m, 2H),1.19-1.16 (m, 2H).

M.N-(6-Bromo-5-chloropyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide

1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride(0.878 g, 3.37 mmol) was placed in an oven-dried flask which was allowedto cool under nitrogen. Dichloromethane (10 mL), triethylamine (1.42 mL,10.1 mmol) and 6-bromo-5-chloropyridin-2-amine (10.1 mmol) were addedand the reaction mixture was stirred for 16 hours. The reaction mixturewas then washed with a saturated aqueous solution of sodium chloride,evaporated to near dryness, and then purified on 40 g of silica gelutilizing a gradient of 0-30% ethyl acetate in hexanes to yieldN-(6-bromo-5-chloropyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(1.01 g, 69%). ESI-MS m/z calc. 429.9, found; 431.3 (M+1)⁺Retention time2.33 minutes.

N.N-(6-Chloro-4-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide

To a solution of 6-chloro-4-methylpyridin-2-amine (300 mg, 2.1 mmol) andEt₃N (1.8 mL, 13 mmol) in dichloromethane (5 mL) was added a solution of1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride(1.6 g, 6.3 mmol) in dichloromethane (5 mL). The resulting reactionmixture was allowed to stir at room temperature for 18 hours. Thereaction mixture was diluted with dichloromethane (10 mL) and was washedwith 1N aqueous HCl (1×20 mL) and saturated aqueous NaHCO₃ (1×20 mL).The organics were dried over sodium sulfate and evaporated to dryness.The resulting residue was purified by silica gel chromatography elutingwith a gradient of 0-70% ethyl acetate in hexane to yieldN-(6-chloro-4-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(700 mg, 91%). ESI-MS m/z calc. 366.1, found 366.9 (M+1)⁺. Retentiontime 2.15 minutes.

O.1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-chloro-5-methylpyridin-2-yl)cyclopropanecarboxamide

Step a: 1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride

To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (100 mg, 0.50mmol) in thionyl chloride (110 μL, 1.5 mmol) was addedN,N-dimethylformamide (20 μL, 0.26 mmol). The reaction mixture wasstirred at room temperature for 30 minutes. Excess thionyl chloride andN,N-dimethylformamide were removed in vacuo and the resulting acidchloride was used directly in next step.

Step b:1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-chloro-5-methylpyridin-2-yl)cyclopropanecarboxamide

To a solution of 6-chloro-5-methylpyridin-2-amine (71 mg, 0.50 mmol) andEt₃N (140 μL, 1.0 mmol) in dichloromethane (2 mL) was added a solutionof 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (110 mg,0.50 mmol) in dichloromethane (2 mL). The resulting reaction mixture wasallowed to stir at room temperature for 18 hours. The reaction mixturewas then washed with 1 N aqueous HCl (1×5 mL) and saturated aqueousNaHCO₃ (1×5 mL). The organic layer was dried over sodium sulfate andevaporated to yield1-(benzo[d][1,3]dioxol-5-yl)-N-(6-chloro-5-methylpyridin-2-yl)cyclopropanecarboxamide(120 mg, 71% over 2 steps). ¹H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H),7.94-7.91 (m, 1H), 7.79-7.77 (m, 1H), 7.09 (m, 1H), 7.00-6.88 (m, 2H),6.06 (s, 2H), 2.25 (s, 3H), 1.47-1.44 (m, 2H), 1.13-1.10 (m, 2H) ESI-MSm/z calc. 330.1, found 331.5 (M+1)⁺. Retention time 1.99 minutes.

P. N-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide

To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride(676 mg, 2.6 mmol) and 6-chloro-4,5-dimethylpyridin-2-amine (314 mg, 2.0mmol), dichloromethane (7.0 mL) and Et₃N (835 μL, 6 mmol) were added.The reaction was stirred at room temperature for 1 hour. The reactionwas diluted with dichloromethane and washed with 1 N HCl (3×) andsaturated aqueous NaHCO₃ (3×). The organic layer was dried overanhydrous Na₂SO₄ and evaporated under reduced pressure. The crudeproduct was purified by column chromatography on silica gel to yieldN-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(560 mg, 73%). ESI-MS m/z calc. 380.07, found 381.3 (M+1)⁺. Retentiontime 2.18 minutes.

Q.N-(6-Chloro-4,5-dimethylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide

To 1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxylic acid (380 mg,1.86 mmol) in thionyl chloride (406.1 μL, 5.580 mmol) was addedN,N-dimethyl formamide (41 μL, 0.53 mmol). The reaction mixture wasstirred at room temperature for 30 minutes before excess thionylchloride and N,N-dimethyl formamide were removed in vacuo to yield theacid chloride. The acid chloride was then dissolved in dichloromethane(5 mL) and added slowly to a solution of6-chloro-4,5-dimethylpyridin-2-amine (350 mg, 2.23 mmol) andtriethylamine (778 μL, 5.58 mmol) in dichloromethane (5 mL). Theresulting reaction mixture was stirred at room temperature for 14 hours.The reaction mixture was diluted with dichloromethane (10 mL) and washedwith 1N aqueous HCl (10 mL) and a saturated aqueous NaHCO₃ solution (10mL). The organic layer was dried over Na₂SO₄, filtered and evaporatedunder reduced pressure. The crude product was purified by columnchromatography on silica gel (0-30% ethyl acetate in hexane) to yieldN-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamideas a pale yellow solid (0.330 g, 51.76%). ESI-MS m/z calc. 342.11, found343.3 (M+1)⁺. Retention time 2.09 minutes.

R.N-(6-Chloro-5-cyano-4-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide

6-Amino-2-chloro-4-methylnicotinonitrile (252 mg, 1.50 mmol) wasdissolved in a mixture of anhydrous N,N′dimethylformamide (DMF, 0.5 mL)and anhydrous tetrahydrofuran (THF, 4.5 mL). The reaction tube wasplaced in a beaker full of room temperature water to help maintain thereaction temperature. Sodium hydride (84.23 mg, 2.106 mmol, 60% byweight in mineral oil) was added and the resulting suspension wasallowed to stir for 5 minutes.1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride(392.0 mg, 1.5 mmol) was added and the reaction mixture turned dark red.The crude material was evaporated to dryness, re-dissolved in a minimumof dichloromethane, and purified on 12 g of silica utilizing a gradientof 0-50% ethyl acetate in hexanes to yield the pure product as a paleyellow solid (0.589 g, 63%). ESI-MS m/z calc. 391.0, found 392.0 (M+1)⁺.Retention time 2.06 minutes.

S.N-(6-Chloro-4-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide

To 1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxylic acid (570 mg,2.8 mmol) in thionyl chloride (0.61 mL, 8.4 mmol) was addedN,N-dimethylformamide (62 μL, 0.80 mmol). The reaction mixture wasstirred for one hour before the excess thionyl chloride andN,N-dimethylformamide were removed in vacuo to yield the acid chlorideas an oil. The acid chloride was then dissolved in dichloromethane (5mL) and was added slowly to a solution of6-chloro-4-methylpyridin-2-amine (400 mg, 2.8 mmol) and triethylamine(1.2 mL, 8.4 mmol) in dichloromethane (5 mL). The resulting reactionmixture was allowed to stir at room temperature overnight. The reactionmixture was diluted with dichloromethane (5 mL) and was washed with 1Naq HCl (10 mL) and then a saturated NaHCO₃ solution (10 mL). Theorganics were dried over Na₂SO₄ and evaporated to dryness. The resultingoil was purified by silica gel chromatography eluting with 0-30% ethylacetate in hexanes to yield the product (770 mg, 84%). ESI-MS m/z calc.328.1, found 329.2 (M+1)⁺. Retention time 1.91 minutes.

T. 6′-Methoxy-3,5′-dimethyl-2,3′-bipyridin-6-amine

6-Chloro-5-methylpyridin-2-amine (1.426 g, 10 mmol),6-methoxy-5-methylpyridin-3-ylboronic acid (2.0 g, 12 mmol) andPd(PPh₃)₄ (577.8 mg, 0.5 mmol) were combined in a flask. DME (100 mL)was added followed by aqueous Na₂CO₃ (10.00 mL of 2 M, 20.0 mmol). Theflask was fitted with a condenser and heated at 80° C. for 12 hoursunder N₂ atmosphere. More Pd(PPh₃)₄ (577.8 mg, 0.5 mmol) was added, thecondenser was removed and the flask was fitted with a rubber stopper. N2(g) was flushed through the flask and the reaction was stirred at 80° C.for an additional 12 hours under N₂(g) balloon. The reaction mixture wasfiltered through a bed of Celite, the Celite was washed with ethylacetate and the combined filtrates were concentrated. The residue waspurified by column chromatography (30-100% ethyl acetate-Hexanes) toyield 680 mg of the product as an orange solid. ¹H NMR (400 MHz,DMSO-d6) δ 8.10 (s, 1H), 7.66 (s, 1H), 7.29 (d, J=8.3 Hz, 1H), 6.37 (d,J=8.3 Hz, 1H), 5.75 (s, 2H), 3.91 (s, 3H), 2.18 (s, 3H), 2.14 (s, 3H).ESI-MS m/z calc. 229.1, found 230.5 (M+1)⁺. Retention time 0.91 minutes.

U.2-Methoxy-3-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

5-Bromo-2-methoxy-3-methylpyridine (400 mg, 2.0 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (610 mg, 2.4mmol), and Pd(dppf)Cl₂ (82 mg, 0.10 mmol) were added to a dry flask andplaced under N₂. Potassium acetate (590 mg, 6.0 mmol) was weigheddirectly into the flask. The flask was then evacuated and back filledwith N₂. Anhydrous N,N-dimethylformamide (DMF) (10 mL) was added and thereaction was heated at 80° C. in an oil bath overnight. The reactionmixture was evaporated to dryness. The residue was dissolved in ethylacetate (20 mL) and washed with water (20 mL). The organics were driedover sodium sulfate and evaporated to dryness. The resulting materialwas purified by silica gel chromatography eluting with 0-70% ethylacetate in hexane to yield2-methoxy-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(360 mg, 72%). ESI-MS m/z calc. 249.1, found 168.3 (MW-C₆H₁₀+1)⁺.Retention time 0.33 minutes.

V.6-Methoxy-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

3-Bromo-6-methoxy-2-methylpyridine (400 mg, 2.0 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (610 mg, 2.4mmol), and Pd(dppf)Cl₂ (82 mg, 0.10 mmol) were added to a dry flask andplaced under N₂. Potassium acetate (590 mg, 6.0 mmol) was weigheddirectly into the flask. The flask was then evacuated and back filledwith N₂. Anhydrous N,N-dimethylformamide (DMF) (10 mL) was added and thereaction was heated at 80° C. in an oil bath overnight. The reactionmixture was evaporated to dryness. The residue was dissolved in ethylacetate (20 mL) and washed with water (20 mL). The organics were driedover sodium sulfate and evaporated to dryness. The resulting materialwas purified by silica gel chromatography eluting with 0-70% ethylacetate in hexane to yield6-methoxy-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(300 mg, 60%). ESI-MS m/z calc. 249.1, found 168.3 (MW-C₆H₁₀+1)⁺.Retention time 0.37 minutes.

W.2-Methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

Step a: 3-Bromo-2-methoxy-5-methylpyridine

To 3-bromo-5-methylpyridin-2-ol (500 mg, 2.7 mmol) and silver carbonate(2.6 g, 9.6 mmol) suspended in dichloromethane (10 mL) was addediodomethane (0.83 mL, 13 mmol). The reaction mixture was allowed to stirat room temperature overnight. The reaction mixture was filtered througha pad of celite and the volatiles were evaporated to yield3-bromo-2-methoxy-5-methylpyridine, which was used directly in the nextstep. ESI-MS m/z calc. 201.0, found 202.3 (M+1)⁺. Retention time 1.51minutes.

Step b:2-Methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

3-Bromo-2-methoxy-5-methylpyridine (540 mg, 2.7 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (810 mg, 3.2mmol), and Pd(dppf)Cl₂ (110 mg, 0.13 mmol) were added to a dry flask andplaced under N₂. Potassium acetate (800 mg, 8.1 mmol) was weigheddirectly into the flask. The flask was then evacuated and back filledwith N₂. Anhydrous N,N-dimethylformamide (DMF) (15 mL) was added and thereaction was heated at 80° C. in an oil bath overnight. The reactionmixture was evaporated to dryness. The residue was dissolved in ethylacetate (20 mL) and washed with water (20 mL). The organics were driedover sodium sulfate and evaporated to dryness. The resulting materialwas purified by silica gel chromatography eluting with 0-100% ethylacetate in hexane to yield2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(450 mg, 67%). ESI-MS m/z calc. 249.1, found 168.3 (MW-C₆H₁₀+1)⁺.Retention time 0.27 minutes. ¹H NMR (400 MHz, CDC₃) δ 8.03 (m, 1H), 7.80(m, 1H), 3.94 (s, 3H), 2.22 (s, 3H), 1.36 (s, 12H).

X.1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one

A mixture of2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (235mg, 1.00 mmol) and CH₃I (426 mg, 3.00 mmol) was heated at 80° C. for 3hours. The mixture was partitioned between ethyl acetate and H₂O. Theaqueous layer was extracted with ethyl acetate and the combined organiclayers were washed with brine, dried over MgSO₄, and evaporated todryness to afford1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-onethat was directly used in next step without further purification.

Y.1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one

Step a: 4-Bromopyridin-2(1H)-one

To a solution of 4-bromo-2-methoxypyridine (1.0 g, 5.3 mmol) in1,4-dioxane (26 mL) was added 4M HCl aqueous solution (13 mL). Thereaction was heated at 90° C. for 5 hours and then at 50° C. overnight.The solution was neutralized with 1N NaOH solution to pH 8-9 andextracted with ethyl acetate. The organics were dried over MgSO₄ andconcentrated to yield 4-bromopyridin-2(1H)— as a white solid (490 mg,53%). The aqueous layer was also concentrated, and then the residue wasstirred with CH₂Cl₂ and filtered. The filtrate was concentrated to yieldadditional 4-bromopyridin-2(1H)— (320 mg, 35%). ESI-MS m/z calc. 173.0,found 174.3 (M+1)⁺. Retention time 0.32 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 11.87 (s, 1H), 7.36 (d, J=7.0 Hz, 1H), 6.64 (d, J=2.0 Hz,1H), 6.37 (dd, J=2.0, 7.0 Hz, 1H).

Step b: 4-Bromo-1-(2-hydroxyethyl)pyridin-2(1H)-one

To a solution of 4-bromopyridin-2(1H)-one (174 mg, 1.00 mmol) in THF(3.5 mL) was added K₂CO₃ (1.38 g, 10.0 mmol) and 2-iodoethanol (156 μL,2.00 mmol). The reaction was stirred at 80° C. for 2 days before beingcooled to room temperature and filtered. The filtrate was concentratedand purified by column chromatography (0-10% MeOH—CH₂Cl₂) to yield4-bromo-1-(2-hydroxyethyl)pyridin-2(1H)-one as a pale yellow solid (30mg, 7%). ESI-MS m/z calc. 217.0, found 218.3 (M+1)⁺. Retention time 0.33minutes. ¹H NMR (400 MHz, DMSO-d6) δ 7.57 (d, J=7.2 Hz, 1H), 6.70 (d,J=2.2 Hz, 1H), 6.44 (dd, J=2.2, 7.2 Hz, 1H), 4.89 (t, J=5.4 Hz, 1H),3.91 (t, J=5.4 Hz, 2H), 3.59 (q, J=5.4 Hz, 2H).

Step c:1-(2-Hydroxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one

A solution of 4-bromo-1-(2-hydroxyethyl)pyridin-2(1H)-one (30 mg, 0.14mmol) in DMSO (1 mL) was added to a flask containing4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (43 mg, 0.17mmol), potassium acetate (41 mg, 0.42 mmol) and Pd(dppf)Cl₂ (6.0 mg,0.0070 mmol). The reaction was stirred under N₂ atmosphere at 80° C.overnight. The reaction was then stirred with ethyl acetate and waterfor 5 minutes before being filtered through Celite. The organic layer ofthe filtrate was washed with H₂O (3×). The intermediate product,1-(2-hydroxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one,was found to be in the aqueous layer. The combined aqueous layers wereconcentrated. The residue was sonicated with DME (1 mL), filtered, andconcentrated to give1-(2-hydroxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one.

Z. Methyl2-(3-cyano-2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-1(2H)-yl)acetate

Step a: 2-(5-Bromo-3-cyano-2-oxopyridin-1(2H)-yl)acetate

To 5-bromo-3-cyano-2(1H)-pyridinone (1.4 g, 7.0 mmol) and potassiumcarbonate (1.9 g, 1.3 mL, 14.1 mmol), THF (26.4 mL) and methylchloroacetate (1.53 g, 1.2 mL, 14.1 mmol) were added. The reaction wasstirred at 80° C. The starting material didn't dissolve well in THF.After 3.5 hours, mainly staring material was observed. DMF (18 mL) wasadded and the starting material went into solution. The reaction washeated at 80° C. for 45 minutes. The desired mass was observed by LCMS.The reaction was filtered using ethyl acetate and the solvent wasevaporated under reduced pressure. The crude product was separated bycolumn chromatography on silica gel (0-100% ethyl acetate in hexane) toyield methyl 2-(5-bromo-3-cyano-2-oxopyridin-1(2H)-yl)acetate as ayellow solid (1.42 g, 74%). ESI-MS m/z calc. 271.07, found 271.3 (M+1)⁺.Retention time 0.59 minutes.

Step b: Methyl2-(3-cyano-2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-1(2H)-yl)acetate

To methyl 2-(5-bromo-3-cyano-2-oxopyridin-1(2H)-yl)acetate (1.42 g, 5.23mmol), bis(pinacol)diboron (1.73 g, 6.81 mmol), potassium acetate (1.54g, 15.72 mmol) and anhydrous DMF (33 mL), Pd(dppf)Cl₂ (0.19 g, 0.26mmol) was added and stirred at 80° C. for 18 hours under N₂. The solventwas evaporated under reduced pressure. To the crude product, ethylacetate (40 mL) and water (40 mL) were added. The biphasic mixture wasfiltered through a plug of celite and the layers were separated. Theorganic layer was dried over Na₂SO₄, filtered and evaporated underreduced pressure. The crude product was purified by columnchromatography on silica gel (0-100% ethyl acetate in hexane) to yieldmethyl2-(3-cyano-2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-1(2H)-yl)acetate.ESI-MS m/z calc. 318.13, found 319.3 (M+1)⁺. Retention time 1.41minutes.

AA.2-Methoxy-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

To 4-bromo-2-methoxy-6-methylpyridine (0.681 g, 3.37 mmoL),bis(pinacol)diboron (1.11 g, 4.38 mmoL), KOAc (0.992 g, 10.11 mmoL) andanhydrous DMF (21 mL), Pd(dppf)Cl₂ (0.120 g, 0.163 mmoL) was added andstirred at 80° C. for 18 hours. The solvent was evaporated under reducedpressure. To the crude product, ethyl acetate (40 mL) and water (40 mL)were added. The biphasic mixture was filtered through a plug of celiteand the layers were separated. The organic layer was dried over Na₂SO₄,filtered and evaporated under reduced pressure. The crude product waspurified by column chromatography on silica gel (0-50% ethyl acetate inhexane) to yield2-methoxy-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.ESI-MS m/z calc. 249.11, found 250.3 (M+1)⁺. Retention time 0.19minutes.

AB.6-Methoxy-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

To 3-bromo-6-methoxy-2-methylpyridine (1.0 g, 4.9 mmol) in N,N-dimethylformamide (30 mL) was added bis(pinacol)diboron (1.5 g, 5.9 mmol),potassium acetate (1.4 g, 14.8 mmol), and Pd(dppf)Cl₂ (202.1 mg, 247.5μmol). The reaction mixture was heated to 80° C. for 18 hours. Thevolatiles were removed to give a black solid which was partitionedbetween ethyl acetate (50 mL) and water (50 mL). The biphasic mixturewas filtered through a pad of celite and the layers separated. Theorganics were dried over Na₂SO₃ and evaporated to dryness. The resultingsolid was purified by silica gel chromatography eluting with 0-30% ethylacetate in hexane to yield6-methoxy-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(0.81 g, 65.7%). ESI-MS m/z calc. 249.11, found 250.5 (M+1)⁺. Retentiontime 1.06 minutes.

AC.2-Methoxy-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

To 5-bromo-2-methoxy-3-methylpyridine (3.14 g, 15.54 mmol) inN,N-dimethyl formamide (90 mL) was added bis(pinacol)diboron (5.13 g,20.20 mmol), potassium acetate (4.58 g, 46.62 mmol), and Pd(dppf)Cl₂(568 mg, 777 μmol). The reaction mixture was heated to 80° C. for 18hours. The volatiles were removed to give a solid which was partitionedbetween ethyl acetate and water. The biphasic mixture was filteredthrough a pad of celite and the layers separated. The organics weredried over Na₂SO₃ and evaporated to dryness. The resulting solid waspurified by silica gel chromatography eluting with 0-30% ethyl acetatein hexane to yield2-methoxy-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(1.35 g, 35%). ESI-MS m/z calc. 249.11, found 250.1 (M+1)⁺. Retentiontime 1.87 minutes.

AD.1-(2-(Methylsulfonyl)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one

Step a: 5-Bromo-1-(2-(methylsulfonyl)ethyl)pyridin-2(1H)-one

5-Bromopyridin-2-ol (4.0 g, 23.0 mmol) and methylsulfonylethene (2.4 g,2.0 mL, 23.0 mmol) were combined in N,N-dimethylformamide (DMF, 23 mL)and heated to 100° C. The crude reaction mixture was then evaporated todryness. The crude material was then dissolved in a minimum ofdichloromethane. The solution was then washed twice with an aqueous 1 Msolution of hydrochloric acid, two times with a saturated aqueoussolution of sodium bicarbonate, two times with a saturated aqueoussolution of sodium chloride, and finally by two washes of water. Theorganic layer was dried over sodium sulfate and then evaporated todryness to yield the product as a pale brown solid (1.87 g, 6.68 mmol,29%). ESI-MS m/z calc. 279.0, found 280.0 (M+1)⁺. Retention time 0.34minutes.

Step b:1-(2-(Methylsulfonyl)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one

5-Bromo-1-(2-(methylsulfonyl)ethyl)pyridin-2(1H)-one (1.7 g, 6.0 mmol),potassium acetate (1.8 g, 18.1 mmol), bis(pinacolato)diboron (2.0 g, 7.8mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (Pd(dppf)Cl₂, 221.1 mg, 0.30 mmol) were combinedin N,N-dimethylformamide (37 mL). The resulting reaction mixture wasstirred and heated to 80° C. for 2 hours. The crude reaction mixture wasevaporated to dryness, partitioned between 250 mL of ethyl acetate and250 mL of water, filtered through celite, and the layers were separated.The organic layer was dried over sodium sulfate and then evaporated todryness. The crude material was purified on silica gel (120 g) utilizinga gradient of 0-10% methanol in dichloromethane to yield the product asa semi-pure brown oil (1.78 g, 5.43 mmol, 90%). ESI-MS m/z calc. 327.1,found 328.2 (M+1)⁺. Retention time 0.90 minutes.

AE.2-(2-Oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-1(2H)-yl)acetonitrile

Step a: 2-(5-Bromo-2-oxopyridin-1(2H)-yl)acetonitrile

2-Hydroxy-5-bromopyridine (5.000 g, 28.74 mmol), potassium carbonate(14.30 g, 9.283 mL, 103.5 mmol), and sodium iodide (1.077 g, 7.185 mmol)were suspended in chloroacetonitrile (10.85 g, 9.095 mL, 143.7 mmol).The reaction mixture was heated to 60° C. and stirred for 2 hours. Thereaction mixture was allowed to cool to room temperature, filtered, andthe filtercake was washed with dichloromethane and ethyl acetate. Thefiltrate was concentrated and purified on 120 g of silica gel utilizinga gradient of 0-100% ethyl acetate in hexanes over 45 minutes to yieldthe pure product as a beige solid (4.1 g, 67%). ¹H NMR (400.0 MHz,DMSO-d₆) δ 8.11 (d, J=2.7 Hz, 1H), 7.63 (dd, J=2.8, 9.8 Hz, 1H), 6.49(d, J=9.8 Hz, 1H), 4.94 (s, 2H).

Step b:2-(2-Oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-1(2H)-yl)acetonitrile

2-(5-Bromo-2-oxopyridin-1(2H)-yl)acetonitrile (2.0 g, 9.4 mmol),potassium acetate (2.77 g, 28.17 mmol), bis(pinacolato)diboron (3.1 g,12.2 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (Pd(dppf)Cl₂, 343.5 mg, 0.47 mmol) werecombined in N,N-dimethylformamide (57 mL). The resulting reactionmixture was stirred and heated to 80° C. for 2 hours. The crude reactionmixture was evaporated to dryness, partitioned between 250 mL of ethylacetate and 250 mL of water, filtered through celite, and the layerswere separated. The organic layer was dried over sodium sulfate and thenevaporated to dryness. The crude material was purified on silica gel (40g) utilizing a gradient of 0-10% methanol in dichloromethane to yieldthe product as a beige solid (0.7722 g, 32%). ESI-MS m/z calc. 260.1,found 261.2 (M+1)⁺. Retention time 1.46 minutes.

AF.3-Chloro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

To a dry flask was added 5-bromo-3-chloro-2-methoxypyridine (0.5 g, 2.2mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.70g, 2.7 mmol), and Pd(dppf)Cl₂ (82 mg, 0.10 mmol). Potassium acetate (0.6g, 6.0 mmol) was weighed directly into the flask. The flask was thenevacuated and back filled with N₂. Anhydrous N,N-dimethylformamide (DMF)(13.0 mL) was added and the reaction was heated at 80° C. in an oil bathovernight. The reaction mixture was evaporated to dryness. The residuewas dissolved in ethyl acetate (10 mL) and washed with water (10 mL).The organics were dried over sodium sulfate and evaporated to dryness.The resulting material was purified by silica gel chromatography(eluting with 0-100% ethyl acetate in hexanes) to yield the product(0.47 g, 78%). ESI-MS m/z calc. 269.53, found 270.3 (MW+1)⁺. Retentiontime 2.07 minutes.

AG.2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

To a dry flask was added 5-bromo-2,3-dimethoxypyridine (0.1 g, 0.46mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.14g, 0.55 mmol), and Pd(dppf)Cl₂ (32 mg, 0.04 mmol). Potassium acetate(0.15 g, 1.5 mmol) was weighed directly into the flask. The flask wasthen evacuated and back filled with N₂. Anhydrous N,N-dimethylformamide(DMF) (2.0 mL) was added and the reaction was heated at 80° C. in an oilbath overnight. The reaction mixture was evaporated to dryness. Theresidue was dissolved in ethyl acetate (5 mL) and washed with water (5mL). The organics were dried over sodium sulfate and evaporated todryness. The resulting material was purified by silica gelchromatography (eluting with 0-100% ethyl acetate in hexanes) to yieldthe product (66 mg, 54%). ESI-MS m/z calc. 265.11, found 266.1 (MW+1)⁺.Retention time 1.53 minutes.

AH. Methyl2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate

To a dry flask was added methyl 5-bromo-2-methoxynicotinate (0.5 g, 2.0mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.61g, 2.4 mmol), and Pd(dppf)Cl₂ (82 mg, 0.10 mmol). Potassium acetate (0.6g, 6.0 mmol) was weighed directly into the flask. The flask was thenevacuated and back filled with N₂. Anhydrous N,N-dimethylformamide (10.0mL) was added and the reaction was heated at 80° C. in an oil bathovernight. The reaction mixture was evaporated to dryness. The residuewas dissolved in ethyl acetate (10 mL) and washed with water (10 mL).The organics were dried over sodium sulfate and evaporated to dryness.The resulting material was purified by silica gel chromatography(eluting with 0-70% ethyl acetate in hexanes) to yield the product (0.36g, 72%). ESI-MS m/z calc. 249.11, found 250.3 (MW+1)⁺. Retention time1.84 minutes.

AI.2-Methoxy-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

To a dry flask was added 5-bromo-2-methoxy-3-nitropyridine (1.3 g, 5.0mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.6g, 6.4 mmol), and Pd(dppf)Cl₂ (0.2 g, 0.25 mmol). Potassium acetate (1.5g, 15 mmol) was weighed directly into the flask. The flask was thenevacuated and back filled with N₂. Anhydrous N,N-dimethylformamide (30mL) was added and the reaction was heated at 80° C. in an oil bathovernight. The reaction mixture was evaporated to dryness. The residuewas dissolved in ethyl acetate (20 mL) and washed with water (20 mL).The organics were dried over sodium sulfate and evaporated to dryness.The resulting material was purified by silica gel chromatography(eluting with 0-50% ethyl acetate in hexane) to yield the product (0.2g, 15%). ESI-MS m/z calc. 280.12, found 199.1 (MW[—C₆H₁₀]+1)⁺. Retentiontime 0.7 minutes.

AJ.5-fluoro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

To a dry flask was added 3-bromo-5-fluoro-2-methoxypyridine (1.0 g, 5.0mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.6g, 6.4 mmol), and Pd(dppf)Cl₂ (0.2 g, 0.25 mmol). Potassium acetate (1.5g, 15 mmol) was weighed directly into the flask. The flask was thenevacuated and back filled with N₂. Anhydrous N,N-dimethylformamide (30mL) was added and the reaction was heated at 80° C. in an oil bathovernight. The reaction mixture was evaporated to dryness. The residuewas dissolved in ethyl acetate (20 mL) and washed with water (20 mL).The organics were dried over sodium sulfate and evaporated to dryness.The resulting material was purified by silica gel chromatography elutingwith 0-50% ethyl acetate in hexane to yield the product (1.0 g, 80%).ESI-MS m/z calc. 253.13, found 254.1 (MW+1)⁺. Retention time 1.72minutes.

AK.5-chloro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

To a dry flask was added 3-bromo-5-chloro-2-methoxypyridine (1.2 g, 5.0mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.6g, 6.4 mmol), and Pd(dppf)Cl₂ (0.2 g, 0.25 mmol). Potassium acetate (1.5g, 15 mmol) was weighed directly into the flask. The flask was thenevacuated and back filled with N₂. Anhydrous N,N-dimethylformamide (30mL) was added and the reaction was heated at 80° C. in an oil bathovernight. The reaction mixture was evaporated to dryness. The residuewas dissolved in ethyl acetate (20 mL) and washed with water (20 mL).The organics were dried over sodium sulfate and evaporated to dryness.The resulting material was purified by silica gel chromatography(eluting with 0-50% ethyl acetate in hexane) to yield the product (0.8g, 60%). ESI-MS m/z calc. 269.10, found 270.3 (MW+1)⁺. Retention time1.95 minutes.

AL.N-(5-Chloro-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide

Step a:N-(3-Chloro-6′-methoxy-2,3′-bipyridin-6-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide

N-(6-Bromo-5-chloropyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(259 mg, 0.600 mmol) was dissolved in 6 mL of 1,2-dimethoxyethane (DME)in a microwave reactor tube. 6-Methoxypyridin-3-ylboronic acid (138 mg,0.900 mmol), 0.6 mL of an aqueous 2 M potassium carbonate solution, andtetrakis(triphenylphospine)palladium(0) (Pd(PPh₃)₄, 34.7 mg, 0.0300mmol) were added and the reaction mixture was heated at 120° C. in amicrowave reactor for 20 minutes. The resulting material was cooled toroom temperature, filtered, and the layers were separated. The crudeproduct was evaporated to dryness and then purified on 40 g of silicagel utilizing a gradient of 0-100% ethyl acetate in hexanes to yieldN-(3-chloro-6′-methoxy-2,3′-bipyridin-6-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (141 mg, 51%) as a colorless oil. ESI-MS m/z calc. 459.1,found; 459.9 (M+1)⁺Retention time 2.26 minutes.

Step b:N-(5-Chloro-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide

N-(3-Chloro-6′-methoxy-2,3′-bipyridin-6-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(124 mg, 0.270 mmol) was dissolved in a mixture of 1.2 mL of 1,4-dioxaneand 0.6 mL of 4M aqueous hydrochloric acid. This solution was heated at90° C. for 5 hours. The crude reaction mixture was quenched withtriethylamine and then evaporated to dryness. The crude product was thenpartitioned between dichloromethane and water. The organic layer wasseparated, dried over sodium sulfate, and then purified on 4 g of silicagel utilizing a gradient of 0-5% methanol in dichloromethane to yieldN-(5-chloro-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide as a white solid (27 mg,22%). ESI-MS m/z calc. 445.1, found 445.9 (M+1)⁺. Retention time 1.62minutes.

AM.1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(2-oxo-1,2-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

Step a:1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (110 mg, 0.300 mmol) wasdissolved in 3 mL of 1,2-dimethoxyethane (DME) in a microwave reactortube. 2-Methoxypyridin-3-ylboronic acid (59.6 mg, 0.390 mmol), 0.4 mL ofan aqueous 2 M potassium carbonate solution, andtetrakis(triphenylphospine)palladium(0) (Pd(PPh₃)₄, 34.7 mg, 0.0300mmol) were added and the reaction mixture was heated at 120° C. in amicrowave reactor for 20 minutes. The resulting material was cooled toroom temperature, filtered, and the layers were separated. The crudeproduct was evaporated to dryness, dissolved in 1 mL ofN,N-dimethylformamide, and purified by reverse-phase preparative liquidchromatography utilizing a gradient of 0-99% acetonitrile in watercontaining 0.05% trifluoracetic acid to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide.ESI-MS m/z calc. 439.1, found 440.1 (M+1)⁺. Retention time 1.94 minutes.

Step b:1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(2-oxo-1,2-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(66 mg, 0.15 mmol) was dissolved in a mixture of 1 mL of 1,4-dioxane and0.5 mL of 4M aqueous hydrochloric acid. This solution was heated at 90°C. for 3 hours. The crude product was then purified by reverse-phasepreparative liquid chromatography utilizing a gradient of 0-99%acetonitrile in water containing 0.05% trifluoracetic acid to yield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(2-oxo-1,2-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide.ESI-MS m/z calc. 425.1, found 426.0 (M+1)⁺. Retention time 1.33 minutes.

AN.1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

Step a:1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (660 mg, 1.80 mmol) wasdissolved in 18 mL of 1,2-dimethoxyethane (DME) in a microwave reactortube. 6-Methoxypyridin-3-ylboronic acid (358 mg, 2.34 mmol), 2.4 mL ofan aqueous 2 M potassium carbonate solution, andtetrakis(triphenylphospine)palladium(0) (Pd(PPh₃)₄, 102 mg, 0.0882 mmol)were added and the reaction mixture was heated at 120° C. in a microwavereactor for 20 minutes. The resulting material was cooled to roomtemperature, filtered, and the layers were separated. The crude productwas evaporated to dryness and then purified on 40 g of silica gelutilizing a gradient of 0-100% ethyl acetate in hexanes to yield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(482 mg, 61%). ESI-MS m/z calc. 439.1, found 440.1 (M+1)⁺Retention time1.95 minutes.

Step b:1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(482 mg, 1.10 mmol) was dissolved in a mixture of 6 mL of 1,4-dioxaneand 3 mL of 4M aqueous hydrochloric acid. This solution was heated at90° C. for 1.5 hours. The crude reaction mixture was quenched with oneequivalent of triethylamine and then evaporated to dryness. The crudeproduct was then partitioned between dichloromethane and water. Theorganic layer was separated, dried over sodium sulfate, and thenpurified on 12 g of silica gel utilizing a gradient of 0-10% methanol indichloromethane to yield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamideas a white solid (189 mg, 40%). ESI-MS m/z calc. 425.1, found 426.3(M+1)⁺. Retention time 1.53 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ 11.78(s, 1H), 8.91 (s, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.66-7.64 (m, 2H),7.56-7.55 (m, 2H), 7.41 (d, J=8.3 Hz, 1H), 7.34 (dd, J=1.7, 8.3 Hz, 1H),6.36 (d, J=9.5 Hz, 1H), 2.28 (s, 3H), 1.52-1.49 (m, 2H), 1.18-1.15 (m,2H).

AO.1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

Step a:1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(73 mg, 0.20 mmol) was dissolved in 2 mL of 1,2-dimethoxyethane in areaction tube.2-Methoxy-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(65 mg, 0.26 mmol), 0.2 mL of an aqueous 2 M sodium carbonate solution,and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.010 mmol) wereadded and the reaction mixture was heated at 80° C. overnight. Thereaction was diluted with ethyl acetate (5 mL) and washed with water (5mL). The organics were dried over sodium sulfate and evaporated todryness. The resulting residue was purified by silica gel chromatographyeluting with 0-100% ethyl acetate in hexane to yield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(46 mg, 51%). ESI-MS m/z calc. 453.4, found 454.3 (M+1)⁺. Retention time2.16 minutes.

Step b:1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

To1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(46 mg, 0.11 mmol) in 1,4-dioxane (1 mL) was added 0.5 mL of an aqueous4 M hydrochloric acid solution. The reaction mixture was heated at 90°C. for 2 hours before being quenched with triethlyamine (0.5 mL). Thereaction mixture was diluted with dichloromethane (3 mL) and washed withwater (3 mL). The organics were dried over sodium sulfate and evaporatedto dryness. The residue was dissolved in N,N-dimethylformamide (1 mL)and purified by reverse-phase preparative liquid chromatography to yield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide as a trifluoroacetic acid salt. ESI-MS m/z calc. 439.4,found 440.3 (M+1)⁺. Retention time 1.64 minutes. ¹H NMR (parent) (400MHz, DMSO-d6) δ 11.68 (s, 1H), 8.93 (s, 1H), 7.80 (d, J=8.3 Hz, 1H),7.64 (d, J=8.4 Hz, 1H), 7.55-7.54 (m, 1H), 7.52-7.51 (m, 1H), 7.41-7.39(m, 2H), 7.34-7.31 (m, 1H), 2.27 (s, 3H), 1.98 (s, 3H), 1.51-1.48 (m,2H), 1.17-1.15 (m, 2H).

AP.1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

Step a:1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-2′,3-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(73 mg, 0.20 mmol) was dissolved in 2 mL of 1,2-dimethoxyethane in areaction tube.6-Methoxy-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(65 mg, 0.26 mmol), 0.2 mL of an aqueous 2 M sodium carbonate solution,and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.010 mmol) wereadded and the reaction mixture was heated at 80° C. overnight. Thereaction was diluted with ethyl acetate (5 mL) and washed with water (5mL). The organics were dried over sodium sulfate and evaporated todryness. The resulting residue was purified by silica gel chromatographyeluting with 0-100% ethyl acetate in hexane to yield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-2′,3-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(69 mg, 76%). ESI-MS m/z calc. 453.4, found 454.3 (M+1)⁺. Retention time1.98 minutes.

Step b:1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

To1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-2′,3-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(69 mg, 0.15 mmol) in 1,4-dioxane (1 mL) was added 0.5 mL of an aqueous4 M hydrochloric acid solution. The reaction mixture was heated at 90°C. for 2 hours before being quenched with triethlyamine (0.5 mL). Thereaction mixture was diluted with dichloromethane (3 mL) and washed withwater (3 mL). The organics were dried over sodium sulfate and evaporatedto dryness. The residue was dissolved in N,N-dimethylformamide (1 mL)and purified by reverse-phase preparative liquid chromatography to yield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide as a trifluoroacetic acid salt. ESI-MS m/z calc. 439.4,found 440.3 (M+1)⁺. Retention time 1.56 minutes. ¹H NMR (parent) (400MHz, DMSO) δ 11.69 (s, 1H), 8.91 (s, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.68(d, J=8.5 Hz, 1H), 7.55 (d, J=1.5 Hz, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.33(dd, J=1.7, 8.3 Hz, 1H), 7.22 (d, J=9.3 Hz, 1H), 6.17 (d, J=9.3 Hz, 1H),2.05 (s, 3H), 1.90 (s, 3H), 1.51-1.48 (m, 2H), 1.17-1.14 (m, 2H).

AQ.1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(5-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

Step a:1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(73 mg, 0.20 mmol) was dissolved in 2 mL of 1,2-dimethoxyethane in areaction tube.2-Methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(65 mg, 0.26 mmol), 0.2 mL of an aqueous 2 M sodium carbonate solution,and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.010 mmol) wereadded and the reaction mixture was heated at 120° C. for 20 minutesunder microwave irradiation. The reaction was diluted with ethyl acetate(5 mL) and washed with water (5 mL). The organics were dried over sodiumsulfate and evaporated to dryness. The resulting residue was purified bysilica gel chromatography eluting with 0-100% ethyl acetate in hexane toyield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(49 mg, 72%). ESI-MS m/z calc. 453.4, found 454.3 (M+1)⁺. Retention time2.10 minutes.

Step b:1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(5-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

To1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(49 mg, 0.11 mmol) in 1,4-dioxane (0.5 mL) was added 0.5 mL of anaqueous 4 M hydrochloric acid solution. The reaction mixture was heatedat 90° C. for 2 hours before being quenched with triethlyamine (0.5 mL).The reaction mixture was diluted with dichloromethane (3 mL) and washedwith water (3 mL). The organics were dried over sodium sulfate andevaporated to dryness. The residue was dissolved inN,N-dimethylformamide (1 mL) and purified by reverse-phase preparativeliquid chromatography to yield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(5-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide as a trifluoroacetic acid salt. ESI-MS m/z calc. 439.4,found 440.3 (M+1)⁺. Retention time 1.55 minutes.

AR.1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,6′-dimethyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide

ToN-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(200 mg, 0.54 mmol),2-methoxy-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(408 mg, 1.64 mmol) and tetrakis(triphenylphosphine)palladium (0) (64mg, 0.055 mmol) in 1,2-dimethoxyethane (3.3 mL), 2 M Na₂CO₃ (818.0 μL,1.636 mmol) was added. The reaction mixture was stirred and heated at80° C. for 68 hours under N₂ atmosphere. The reaction mixture wasdiluted with ethyl acetate (5 mL), dried over Na₂SO₄, filtered andevaporated under reduced pressure. The crude product was purified bycolumn chromatography on silica gel (0-15% ethyl acetate in hexane) toyield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,6′-dimethyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide(0.214 g, 86.5%). ESI-MS m/z calc. 453.4, found 454.5 (M+1)⁺. Retentiontime 1.81 minutes.

AS.1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(6-methyl-2-oxo-1,2-dihydropyridin-4-yl)pyridin-2-yl)cyclopropanecarboxamide

To a suspension of1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,6′-dimethyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide(12 mg, 26.5 μmol) in CH₃CN (0.5 mL) was added TMSI (7.5 μL, 52.9 μmol)drop wise. The reaction was stirred at 55° C. for 1 hour. MeOH (1.0 mL)was added followed by ethyl acetate (3 mL) and water (1 mL). The organiclayer was separated and washed with NaHSO₃ (2×), and brine (1×). Theorganic layer was then dried over Na₂SO₄, filtered and evaporated underreduced pressure to yield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(6-methyl-2-oxo-1,2-dihydropyridin-4-yl)pyridin-2-yl)cyclopropanecarboxamideas a white solid (9.5 g, 81.7%); ESI-MS m/z calc. 439.4, found 440.5(M+1)⁺. Retention time 1.60 minutes.

AT. Methyl2-(3-cyano-5-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-2-oxopyridin-1(2H)-yl)acetate

ToN-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(150 mg, 0.41 mmol), methyl2-(3-cyano-2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-1(2H)-yl)acetate(244 mg, 0.61 mmol) and tetrakis(triphenylphosphine)palladium (0) (47mg, 0.041 mmol) in 1,2-dimethoxyethane (4.5 mL), 2 M Na₂CO₃ (613.5 μL,1.23 mmol) was added. The reaction mixture was stirred and heated at 80°C. for 22 hours under N₂ atmosphere. The reaction mixture was dilutedwith ethyl acetate (5 mL), dried over Na₂SO₄, filtered and evaporatedunder reduced pressure. The crude product was purified by columnchromatography on silica gel (0-100% ethyl acetate in hexane) to yieldmethyl2-(3-cyano-5-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-2-oxopyridin-1(2H)-yl)acetate(100 mg, 46.8%). ESI-MS m/z calc. 522.5, found 532.5 (M+1)⁺. Retentiontime 1.86 minutes.

AQ.1-(4-Methoxyphenyl)-N-(5-methyl-6-(2-oxo-1,2-dihydropyridin-4-yl)pyridin-2-yl)cyclopropanecarboxamide

Step a:N-(2′-Methoxy-3-methyl-2,4′-bipyridin-6-yl)-1-(4-methoxyphenyl)-cyclopropanecarboxamide

N-(6-Chloro-5-methylpyridin-2-yl)-1-(4-methoxyphenyl)cyclopropanecarboxamide (63 mg, 0.20 mmol) was dissolved in 1,2-dimethoxyethane (2.0mL) in a reaction tube. 2-Methoxypyridin-4-ylboronic acid (46 mg, 0.30mmol), aqueous 2 M sodium carbonate (0.20 mL), and (Ph₃P)₄Pd (12 mg,0.010 mmol) were added and the reaction mixture was heated at 80° C.under N₂ atmosphere for 18 hours. Since the reaction was incomplete, itwas re-treated with same amount of boronic acid, base and Pd catalystand heated at 80° C. for 18 hours. The resulting material was cooled toroom temperature, filtered, and evaporated under reduced pressure. Thecrude product was dissolved in DMSO (2 mL), filtered, and purified byreverse phase preparative HPLC to yieldN-(2′-methoxy-3-methyl-2,4′-bipyridin-6-yl)-1-(4-methoxyphenyl)cyclopropanecarboxamide. ESI-MS m/z calc. 389.2, found 390.5 (M+1)⁺. Retention time1.84 minutes.

Step b:1-(4-Methoxyphenyl)-N-(5-methyl-6-(2-oxo-1,2-dihydropyridin-4-yl)pyridin-2-yl)cyclopropanecarboxamide

N-(2′-Methoxy-3-methyl-2,4′-bipyridin-6-yl)-1-(4-methoxyphenyl)cyclopropanecarboxamide(TFA salt) (˜39 mg, ˜0.10 mmol) was dissolved in chloroform (1 mL) in areaction tube. Trimethylsilyliodide (56 μL, 0.40 mmol was added and thereaction mixture was stirred at room temperature for 4 hours. Theresulting material was filtered and evaporated under reduced pressure.The crude product was dissolved in DMSO (1 mL), filtered, and purifiedby reverse phase preparative HPLC to yield1-(4-methoxyphenyl)-N-(5-methyl-6-(2-oxo-1,2-dihydropyridin-4-yl)pyridin-2-yl)cyclo-propanecarboxamide.ESI-MS m/z calc. 375.2, found 376.5 (M+1)⁺. Retention time 1.45 minutes.

AR.1-(4-Methoxyphenyl)-N-(5-methyl-6-(2-oxo-1,2-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

Step a:N-(2′-Methoxy-3-methyl-2,3′-bipyridin-6-yl)-1-(4-methoxyphenyl)cyclopropanecarboxamide

N-(6-Chloro-5-methylpyridin-2-yl)-1-(4-methoxyphenyl)cyclopropanecarboxamide (63 mg, 0.20 mmol) was dissolved in 1,2-dimethoxyethane (2.0mL) in a reaction tube. 2-Methoxypyridin-3-ylboronic acid (46 mg, 0.30mmol), aqueous 2 M sodium carbonate (0.20 mL), and (Ph₃P)₄Pd (12 mg,0.010 mmol) were added and the reaction mixture was heated at 80° C.under N₂ atmosphere for 18 hours. Since the reaction was incomplete, itwas re-treated with same amount of boronic acid, base and Pd catalystand was heated at 80° C. for 18 hours. The resulting material was cooledto room temperature, filtered, and evaporated under reduced pressure.The crude product was dissolved in DMSO (2 mL), filtered and purified byreverse phase preparative HPLC to yieldN-(2′-methoxy-3-methyl-2,3′-bipyridin-6-yl)-1-(4-methoxyphenyl)cyclopropanecarboxamide. ESI-MS m/z calc. 389.2, found 390.5 (M+1)⁺. Retention time1.76 minutes.

Step b:1-(4-Methoxyphenyl)-N-(5-methyl-6-(2-oxo-1,2-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

N-(2′-Methoxy-3-methyl-2,3′-bipyridin-6-yl)-1-(4-methoxyphenyl)cyclopropanecarboxamide (TFA salt) (˜39 mg, ˜0.10 mmol) was dissolved in 1,4-dioxane(0.6 mL) in a reaction tube. An aqueous 4M HCl (0.27 mL, 1.1 mmol) wasadded and the reaction mixture was stirred at 90° C. for 1 hour. Theresulting material was cooled to room temperature, filtered, andpurified by reverse phase preparative HPLC to yield1-(4-methoxyphenyl)-N-(5-methyl-6-(2-oxo-1,2-dihydropyridin-3-yl)pyridin-2-yl)cyclo-propanecarboxamide.ESI-MS m/z calc. 375.2, found 376.7 (M+1)⁺. Retention time 1.26 minutes.¹H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.66(d, J=8.4 Hz, 1H), 7.47-7.42 (m, 3H), 7.38 (dd, J=6.8, 2.1 Hz, 1H), 6.98(d, J=8.7 Hz, 2H), 6.25 (t, J=6.6 Hz, 1H), 3.77 (s, 3H), 2.08 (s, 3H),1.52-1.49 (m, 2H), 1.13-1.11 (m, 2H).

AM.1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

Step a:1-(Benzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-chloro-5-methylpyridin-2-yl)cyclopropanecarboxamide(66 mg, 0.20 mmol) was dissolved in 2 mL of 1,2-dimethoxyethane in areaction tube. 6-Methoxypyridin-3-ylboronic acid (37 mg, 0.24 mmol), 0.2mL of an aqueous 2 M sodium carbonate solution, andtetrakis(triphenylphosphine)palladium(0) (12 mg, 0.010 mmol) were addedand the reaction mixture was heated at 80° C. overnight. The reactionwas diluted with ethyl acetate (5 mL) and washed with water (5 mL). Theorganics were dried over sodium sulfate and evaporated to dryness. Theresulting residue was purified by silica gel chromatography eluting witha gradient of 0-100% ethyl acetate in hexane to yield1-(benzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclo-propanecarboxamide(34 mg, 51%). ESI-MS m/z calc. 403.2, found 404.7 (M+1)⁺. Retention time1.84 minutes.

Step b:1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

To1-(benzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(34 mg, 0.080 mmol) in 1,4-dioxane (1 mL) was added 0.5 mL of an aqueous4 M hydrochloric acid solution. The reaction mixture was heated at 90°C. for 4 hours before being quenched with triethlyamine (0.5 mL) andevaporated to dryness. The residue was dissolved inN,N-dimethylformamide (1 mL) and purified by reverse-phase preparativeliquid chromatography to yield1-(benzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamideas a trifluoroacetic acid salt. ESI-MS m/z calc. 389.1, found 390.3(M+1)⁺. Retention time 2.00 minutes.

AN.1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(4-methyl-6-(2-oxo-1,2-dihydropyridin-4-yl)pyridin-2-yl)cyclopropanecarboxamide

Step a:1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-4-methyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide

N-(6-Chloro-4-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(73 mg, 0.20 mmol) was dissolved in 2 mL of 1,2-dimethoxyethane in areaction tube.2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (55mg, 0.36 mmol), 0.3 mL of an aqueous 2 M sodium carbonate solution, andtetrakis(triphenylphosphine)palladium(0) (18 mg, 0.015 mmol) were addedand the reaction mixture was heated at 80° C. overnight. The reactionmixture was diluted with dichloromethane (5 mL) and washed with water (5mL). The organics were dried over sodium sulfate and evaporated todryness. The resulting residue was purified by silica gel chromatographyeluting with a gradient of 0-100% ethyl acetate in hexane to yield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-4-methyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide(31 mg, 35%). ESI-MS m/z calc. 439.1, found 440.3 (M+1)⁺. Retention time2.12 minutes.

Step b:1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(4-methyl-6-(2-oxo-1,2-dihydropyridin-4-yl)pyridin-2-yl)cyclopropanecarboxamide

To1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-4-methyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide(31 mg, 0.070 mmol) in chloroform (1 mL) was added iodotrimethylsilane(30 μL, 0.21 mmol). The reaction mixture was stirred at room temperatureovernight. The reaction mixture was evaporated to dryness and theresidue was dissolved in N,N-dimethylformamide (1 mL) and purified byreverse-phase preparative liquid chromatography to yield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(4-methyl-6-(2-oxo-1,2-dihydropyridin-4-yl)pyridin-2-yl)cyclopropanecarboxamideas the trifluoroacetic acid salt. ESI-MS m/z calc. 425.1, found 426.3(M+1)⁺. Retention time 1.70 minutes.

AO.1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

To a mixture of1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one(68 mg, 0.30 mmol),N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(88 mg, 0.24 mmol) in DME (1.5 mL) and 2 M Na₂CO₃ (0.24 mL) was addedPd(PPh₃)₄ (14 mg, 0.0030 mmol). The mixture was heated in microwave ovenat 120° C. for 30 min. The mixture was partitioned between ethyl acetateand H₂O before the aqueous layer was extracted with ethyl acetate (3×).The combined organic layers were washed with brine and dried over MgSO₄.After the removal solvent, the residue was purified by columnchromatography (10-20% EtOAc-Hexane) to afford1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide(67 mg, 72%). ¹H-NMR (400 MHz, CDC₃) 6.8.06 (d, J=8.4 Hz, 1H), 7.63 (s,1H), 7.57 (d, J=8.4 Hz, 1H), 7.53-7.48 (m, 2H), 7.24 (td, J=10.0, 1.7Hz, 2H), 7.12 (d, J=8.2 Hz, 1H), 6.61 (d, J=9.2 Hz, 1H), 3.60 (s, 3H),2.33 (s, 3H), 1.77 (q, J=3.6 Hz, 2H), 1.19 (q, J=3.6 Hz, 2H). MS (ESI)m/e (M+H⁺) 440.2.

AP. 1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl) N (6 (1 (2hydroxyethyl)-2-oxo-1,2-dihydropyridin-4-yl)-5-methylpyridin-2-yl)cyclopropanecarboxamide

1-(2-Hydroxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one(0.14 mmol) was added to a microwave vial containingN-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(51 mg, 0.14 mmol) and Pd(PPh₃)₄ (8.0 mg, 0.0070 mmol). Saturatedaqueous Na₂CO₃ (70 μL) was added and the reaction vial was flushed withN₂ (g) and sealed. The reaction was heated in the microwave at 120° C.for 20 minutes before being filtered and concentrated. The residue wasdissolved in DMSO and purified by reverse-phase HPLC to yield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(1-(2-hydroxyethyl)-2-oxo-1,2-dihydropyridin-4-yl)-5-methylpyridin-2-yl)cyclopropanecarboxamide.ESI-MS m/z calc. 469.1, found 470.5 (M+1)⁺. Retention time 1.58 minutes.¹H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.73(d, J=8.5 Hz, 1H), 7.63 (d, J=6.9 Hz, 1H), 7.56 (d, J=1.6 Hz, 1H), 7.41(d, J=8.3 Hz, 1H), 7.34 (dd, J=1.7, 8.3 Hz, 1H), 6.39 (d, J=1.8 Hz, 1H),6.26 (dd, J=1.9, 6.9 Hz, 1H), 3.96 (t, J=5.4 Hz, 2H), 3.63 (t, J=5.5 Hz,2H), 2.26 (s, 3H), 1.52-1.50 (m, 2H), 1.19-1.16 (m, 2H).

AQ.1-(2,3-dihydro-1H-inden-5-yl)-N-(5-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

Step a:N-(6-chloro-5-methylpyridin-2-yl)-1-(2,3-dihydro-1H-inden-5-yl)cyclopropanecarboxamide

To 1-(2,3-dihydro-1H-inden-5-yl)cyclopropanecarboxylic acid (0.2 g,0.9889 mmol) in thionyl chloride (215.9 μL, 2.967 mmol) was addedN,N-dimethyl formamide (21.79 μL, 0.2826 mmol). The reaction mixture wasstirred at room temperature for 30 minutes before excess thionylchloride and N,N-dimethyl formamide were removed in vacuo to yield theacid chloride. The acid chloride was then dissolved in dichloromethane(3 mL) and added slowly to a solution of6-chloro-5-methylpyridin-2-amine (0.169 g, 1.187 mmol) and triethylamine(413.5 μL, 2.967 mmol) in dichloromethane (3 mL). The resulting reactionmixture was stirred at room temperature for 17.5 hours. The reactionmixture was diluted with dichloromethane (10 mL) and washed first with1N aqueous HCl (10 mL) and then with a saturated aqueous NaHCO₃ solution(10 mL). The organic layer was dried over Na₂SO₄, filtered andevaporated under reduced pressure. The crude product was purified bycolumn chromatography on silica gel (0-30% ethyl acetate in hexane) toyieldN-(6-chloro-5-methylpyridin-2-yl)-1-(2,3-dihydro-1H-inden-5-yl)cyclopropanecarboxamide(0.135 g, 41.77%). ESI-MS m/z calc. 326.12, found 327.5 (M+1)⁺.Retention time 2.33 minutes.

Step b:1-(2,3-Dihydro-1H-inden-5-yl)-N-(6′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

ToN-(6-chloro-5-methylpyridin-2-yl)-1-(2,3-dihydro-1H-inden-5-yl)cyclopropanecarboxamide(0.132 g, 0.4030 mmol), 6-methoxypyridin-3-ylboronic acid (0.092 g,0.6045 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.046 g,0.04030 mmol) in 1,2-dimethoxyethane (4.4 mL), 2 M Na₂CO₃ (600 μL) wasadded. The reaction mixture was stirred and heated at 80° C. for 22hours under N₂ atmosphere. The reaction mixture was diluted with ethylacetate (5 mL), dried over Na₂SO₄, filtered and evaporated under reducedpressure. The crude product was purified by column chromatography onsilica gel (0-30% ethyl acetate in hexane) to yield1-(2,3-dihydro-1H-inden-5-yl)-N-(6′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamideas a white solid (0.150 g, 93.17%). ESI-MS m/z calc. 399.48, found 400.5(M+1)⁺. Retention time 2.17 minutes.

Step c:1-(2,3-dihydro-1H-inden-5-yl)-N-(5-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

To a suspension of1-(2,3-dihydro-1H-inden-5-yl)-N-(6′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(0.127 g, 0.3172 mmol) in CH₃CN (6.7 mL) was added TMSI (254 mg, 180.5μL, 1.27 mmol) drop-wise. The suspension became a clear solution uponTMSI addition. The reaction was stirred at 55° C. for 6.5 hours. Thereaction was allowed to cool down to room temperature. Methanol (2.0 mL)was added followed by ethyl acetate (6 mL). The organic layer was washedwith NaHSO₃ (2×), and brine (1×). The organic layer was dried overNa₂SO₄, filtered and evaporated under reduced pressure. The crudeproduct was purified by column chromatography on silica gel (0-10%methanol in dichloromethane) to yield1-(2,3-dihydro-1H-inden-5-yl)-N-(5-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamideas a yellow solid (0.096 g, 78.5%). ESI-MS m/z calc. 385.46, found 386.5(M+1)⁺. Retention time 1.58 minutes.

AR.1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(1-(2-hydroxyethyl)-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)-5-methylpyridin-2-yl)cyclopropanecarboxamide

Step a:1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

To a mixture ofN-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(0.550 g, 1.5 mmol) and 6-methoxy-4-methylpyridin-3-ylboronic acid(0.376 g, 2.25 mmol) in DME (10 mL) and Na₂CO₃ (2 M, 1.5 mL, 3.0 mmol)was added Pd(PPh₃)₄ (0.087 g, 0.075 mmol). The mixture was heated inmicrowave oven at 120° C. for 30 minutes. The reaction was partitionedbetween ethyl acetate and water and the aqueous layer was extracted withethyl acetate twice. The combined organic layers were washed with brineand dried over MgSO₄. After the removal of solvent, the residue waspurified by column chromatography (0-20% EtOAc-Hexane) to yield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(0.554 g, 81%). ESI-MS m/z calc. 453.44, found 454.2 (M+1)⁺. Retentiontime 2.08 minutes.

Step b:1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-hydroxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

To a mixture of1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(0.181 g, 0.05 mmol) in CH₃CN (0.5 mL) was added TMSI (114, 0.80 mmol)drop wise at 0° C. The reaction was stirred at 50° C. for 3 hours. Thereaction was partitioned between ethyl acetate and H₂O and the aqueouslayer was extracted with ethyl acetate. The combined organic layers werewashed with brine and dried over MgSO₄. After the removal of solvent,the residue was purified by column chromatography (0-10% MeOH-EtOAc) toyield a yellow solid. The solid was re-dissolved in DCM-EtOAc, washedwith NaHSO₃ (2×), brine, dried over MgSO₄ and evaporated to dryness toyield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-hydroxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamideas a white solid (0.148 g, 84%). ESI-MS m/z calc. 439.41, found 440.2(M+1)⁺. Retention time 1.51 minutes.

Step c: Methyl2-(3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-5-methyl-2-oxopyridin-1(2H)-yl)acetate

To a solution of1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-hydroxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(0.029 g, 0.06556 mmol) in DMF (1 mL) was added K₂CO₃ (0.091 mg, 0.6556mmol) and methyl chloroacetate (28.82 μL, 0.3278 mmol). The reaction wasstirred at 80° C. for 21 hours to yield a mixture of N-alkylated productand O-alkylated product. The reaction was filtered using ethyl acetateand the solvent was evaporated under reduced pressure. The crudeproducts were separated by column chromatography on silica gel (0-100%ethyl acetate in hexane) to yield methyl2-(3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-5-methyl-2-oxopyridin-1(2H)-yl)acetate[20mg, 59.3%; ESI-MS m/z calc. 511.47, found 512.5 (M+1)⁺, retention time1.74 minutes] and methyl2-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3,5′-dimethyl-2,3′-bipyridin-2′-yloxy)acetate[8mg, 24%; ESI-MS m/z calc. 511.47, found 512.5 (M+1)⁺, retention time2.13 minutes].

Step d:1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(1-(2-hydroxyethyl)-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)-5-methylpyridin-2-yl)cyclopropanecarboxamide

To a solution of methyl2-(3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-5-methyl-2-oxopyridin-1(2H)-yl)acetate(17 mg, 0.034 mmol) in THF (1.6 mL) was added NaBH₄ (7 mg, 0.17 mmol)and stirred at 50° C. for 3 hours and 15 minutes. The reaction wasfiltered using ethyl acetate and the solvent was evaporated underreduced pressure. The crude product was purified by columnchromatography on silica gel (0-100% ethyl acetate in hexane) to yield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(1-(2-hydroxyethyl)-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)-5-methylpyridin-2-yl)cyclopropanecarboxamideas a white solid (5.5 g, 33.6%). ESI-MS m/z calc. 483.46, found 484.5(M+1)⁺, retention time 1.49 minutes

AS.1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,6′-dimethyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide

ToN-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(200 mg, 0.545 mmol),2-methoxy-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(408 mg, 1.636 mmol) and tetrakis(triphenylphosphine)palladium (0) (64mg, 0.055 mmol) in 1,2-dimethoxyethane (3.3 mL), 2 M Na₂CO₃ (818.0 μL,1.63 mmol) was added. The reaction mixture was stirred and heated at 80°C. for 68 hours under N₂ atmosphere. The reaction mixture was dilutedwith ethyl acetate (5 mL), dried over Na₂SO₄, filtered and evaporatedunder reduced pressure. The crude product was purified by columnchromatography on silica gel (0-15% ethyl acetate in hexane) to yield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,6′-dimethyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide(214 mg, 86.5%). ESI-MS m/z calc. 453.4, found 454.5 (M+1)⁺, retentiontime 1.81 minutes.

AT.1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(6-methyl-2-oxo-1,2-dihydropyridin-4-yl)pyridin-2-yl)cyclopropanecarboxamide

To a suspension of1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,6′-dimethyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide(0.012 g, 26.46 μmol) in CH₃CN (0.5 mL) was added TMSI (7.5 μL, 52.9μmol) drop wise. The reaction was stirred at 55° C. for 1 hour. MeOH(1.0 mL) was added followed by ethyl acetate (3 mL) and water (1 mL).The organic layer was separated and washed with NaHSO₃ (2×) and brine(1×). The organic layer was then dried over Na₂SO₄, filtered andevaporated under reduced pressure to yield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(6-methyl-2-oxo-1,2-dihydropyridin-4-yl)pyridin-2-yl)cyclopropanecarboxamideas a white solid (9.5 mg, 81.7%). ESI-MS m/z calc. 439.4, found 440.5(M+1)⁺, retention time 1.60 minutes

AU.1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(4-methyl-6-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

Step a:1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-2′,4-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

To N-(6-chloro-4-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (88 mg, 0.24 mmol) in1,2-dimethoxyethane (2.5 mL) was added6-methoxy-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(144 mg, 0.29 mmol), tetrakis(triphenylphosphine)palladium (0) (28 mg,0.024 mmol), and 2 M Na₂CO₃ (361.2 μL, 0.72 mmol). The reaction mixturewas irradiated in the microwave at 120° C. for 20 minutes. The reactionmixture was evaporated to dryness and purified by silica gelchromatography eluting with (0-20% ethyl acetate in hexane) to yield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-2′,4-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(70 mg, 61%). ESI-MS m/z calc. 453.44, found 454.3 (M+1)⁺. Retentiontime 1.89 minutes.

Step b:1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(4-methyl-6-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-2′,4-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(70 mg, 0.154 mmol) in 1,4-dioxane (1.9 mL) was added aqueous 4 M HCl(417 μL, 1.67 mmol) drop-wise. The reaction was stirred at 90° C. for1.5 hours. The reaction was allowed to cool down to room temperature andthen quenched with Et₃N. The solvent was evaporated under reducedpressure. The crude compound was dissolved in ethyl acetate and washedwith water (2×) and brine (1×). The organic layer was dried over Na₂SO₄,filtered and evaporated under reduced pressure. The crude product waspurified by column chromatography on silica gel (0-100% ethyl acetate inhexane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(4-methyl-6-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamideas a yellow solid (13 mg, 20%); ESI-MS m/z calc. 439.41, found 440.5(M+1)⁺. Retention time 1.58 minutes.

AV.1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(4-methyl-6-(4-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

Step a:1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-4,4′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

ToN-(6-chloro-4-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(59 mg, 0.16 mmol), 6-methoxy-4-methylpyridin-3-ylboronic acid (40 mg,0.24 mmol) and tetrakis(triphenylphosphine)palladium (0) (9 mg, 0.008mmol) in 1,2-dimethoxyethane (1.63 mL), aqueous saturated Na₂CO₃ (163uL) was added. The reaction mixture was stirred and heated at 80° C. for18 hours under N₂ atmosphere. The reaction mixture was diluted with1,2-dimethoxyethane, dried over Na₂SO₄, filtered and evaporated underreduced pressure. The crude product was purified by columnchromatography on silica gel (0-30% ethyl acetate in hexane) to yield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-4,4′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(38 mg, 52%). ESI-MS m/z calc. 453.44, found 454.5 (M+1)⁺. Retentiontime 2.01 minutes.

Step b:1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(4-methyl-6-(4-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-4,4′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(38 mg, 0.083 mmol) in 1,4-dioxane (1.5 mL) was added aqueous 4 M HCl(225 μL, 0.899 mmol) drop-wise. The reaction was stirred at 90° C. for1.5 hours. The reaction was allowed to cool down to room temperature andthen quenched with Et₃N. The solvent was evaporated under reducedpressure. The crude compound was dissolved in ethyl acetate and washedwith water (2×) and brine (1×). The organic layer was dried over Na₂SO₄,filtered and evaporated under reduced pressure. The crude product waspurified by column chromatography on silica gel (0-10% methanol indichloromethans) to yield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(4-methyl-6-(4-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamideas a white solid (7 mg, 19%). ESI-MS m/z calc. 439.41, found 440.5(M+1)⁺. Retention time 1.60 minutes.

AW.1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(4-methyl-6-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

Step a:1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-4,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

ToN-(6-chloro-4-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(0.15 g, 0.41 mmol),2-methoxy-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(0.15 g, 0.61 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.024g, 0.02 mmol) in 1,2-dimethoxyethane (2.46 mL), aqueous saturated Na₂CO₃(410 uL) was added. The reaction mixture was stirred and heated at 80°C. for 18 hours under N₂ atmosphere. The reaction mixture was dilutedwith 1,2-dimethoxyethane, dried over Na₂SO₄, filtered and evaporatedunder reduced pressure. The crude product was purified by columnchromatography on silica gel (0-30% ethyl acetate in hexane) to yield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-4,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(0.075 g, 40%). ESI-MS m/z calc. 453.44, found 454.5 (M+1)⁺. Retentiontime 2.24 minutes.

Step b:1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(4-methyl-6-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

To1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-4,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(0.075 g, 0.165 mmol) in 1,4-dioxane (2 mL) was added aqueous 4 M HCl(447 μL, 1.79 mmol) drop-wise. The reaction was stirred at 90° C. for1.5 hours. The reaction was allowed to cool down to room temperature andthen quenched with Et₃N. The solvent was evaporated under reducedpressure. The crude compound was dissolved in ethyl acetate and washedwith water (2×) and brine (1×). The organic layer was dried over Na₂SO₄,filtered and evaporated under reduced pressure. The crude product waspurified by column chromatography on silica gel (0-100% ethyl acetate inhexane) to yield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(4-methyl-6-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamideas a white solid (33 mg, 46%); ESI-MS m/z calc. 439.41, found 440.5(M+1)⁺. Retention time 1.72 minutes.

AX.1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-2′,3,4-trimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

To N-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (70 mg, 0.18 mmol),6-methoxy-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(69 mg, 0.27 mmol) and tetrakis(triphenylphosphine)-palladium (0) (21mg, 0.018 mmol) in 1,2-dimethoxyethane (2.0 mL), 2 M Na₂CO₃ (276 μL,0.55 mmol) was added. The reaction mixture was stirred and heated at 80°C. for 20 hours under N₂ atmosphere. The reaction mixture was dilutedwith ethyl acetate (5 mL), dried over Na₂SO₄, filtered and evaporatedunder reduced pressure. The crude product was purified by columnchromatography on silica gel (0-30% ethyl acetate in hexane) to yield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-2′,3,4-trimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(45 mg, 52%). ESI-MS m/z calc. 467.5, found 468.3 (M+1)⁺. Retention time1.80 minutes.

AY.1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(4,5-dimethyl-6-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

To a suspension of1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-2′,3,4-trimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(41.6 mg, 0.09 mmol) in CH₃CN (1.8 mL) was added TMSI (25.3 μL, 0.18mmol) drop wise. The suspension became clear solution on TMSI addition.The reaction was stirred at 55° C. for 2 hours and 30 minutes. Thereaction was allowed to cool down to room temperature. Methanol (1.0 mL)was added followed by ethyl acetate (6 mL). The organic layer was washedwith NaHSO₃ (2×), and brine (1×). The organic layer was dried overNa₂SO₄, filtered and evaporated under reduced pressure. The crudeproduct was purified by column chromatography on silica gel (0-10%methanol in dichloromethane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(4,5-dimethyl-6-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamideas a white solid (30 mg, 74%). ESI-MS m/z calc. 453.4, found 454.3(M+1)⁺. Retention time 1.50 minutes.

AZ.1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3,4,5′-trimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

ToN-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(70 mg, 0.18 mmol),2-methoxy-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(69 mg, 0.27 mmol) and tetrakis(triphenylphosphine)palladium (0) (21 mg,0.018 mmol) in 1,2-dimethoxyethane (2.0 mL), 2 M Na₂CO₃ (276 μL, 0.55mmol) was added. The reaction mixture was stirred and heated at 80° C.for 20 hours under N₂ atmosphere. The reaction mixture was diluted withethyl acetate (5 mL), dried over Na₂SO₄, filtered and evaporated underreduced pressure. The crude product was purified by columnchromatography on silica gel (0-30% ethyl acetate in hexane) to yield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3,4,5′-trimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(50 mg, 58%). ESI-MS m/z calc. 467.4, found 468.7 (M+1)⁺. Retention time1.96 minutes.

BA.1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(4,5-dimethyl-6-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

To a suspension of1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3,4,5′-trimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(44 mg, 0.09 mmol) in CH₃CN (2.0 mL) was added TMSI (27 μL, 0.19 mmol)drop wise. The reaction was stirred at 55° C. for 2 hours and 30minutes. The reaction was allowed to cool down to room temperature.Methanol (1.0 mL) was added followed by ethyl acetate (6 mL). Theorganic layer was washed with NaHSO₃ (2×), and brine (1×). The organiclayer was dried over Na₂SO₄, filtered and evaporated under reducedpressure. The crude product was purified by column chromatography onsilica gel (0-10% methanol in dichloromethane) to yield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(4,5-dimethyl-6-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamideas a white solid (37 mg, 86%). ESI-MS m/z calc. 453.4, found 454.5(M+1)⁺. Retention time 1.58 minutes.

BB.1-(2,3-Dihydrobenzofuran-5-yl)-N-(2′-methoxy-3,4-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

ToN-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide(100 mg, 0.29 mmol), 2-methoxypyridin-3-ylboronic acid (67 mg, 0.44mmol) and tetrakis(triphenylphosphine)palladium (0) (34 mg, 0.029 mmol)in 1,2-dimethoxyethane (3.0 mL), 2 M Na₂CO₃ (438 μL, 0.88 mmol) wasadded. The reaction mixture was stirred and heated at 80° C. for 68hours under N₂ atmosphere. The reaction mixture was diluted with ethylacetate (5 mL), dried over Na₂SO₄, filtered and evaporated under reducedpressure. The crude product was purified by column chromatography onsilica gel (0-30% ethyl acetate in hexane) to yield1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-3,4-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamideas a pale yellow solid (112 mg, 92.4%). ESI-MS m/z calc. 415.5, found416.5 (M+1)⁺. Retention time 1.68 minutes.

BC.1-(2,3-Dihydrobenzofuran-5-yl)-N-(4,5-dimethyl-6-(2-oxo-1,2-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

To a suspension of1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-3,4-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(105 mg, 0.25 mmol) in CH₃CN (5.0 mL) was added TMSI (71.7 μL, 0.50mmol) drop wise. The reaction was stirred at 55° C. for 1 hour. Methanol(1.0 mL) was added followed by ethyl acetate (6 mL). The organic layerwas washed with NaHSO₃ (2×), and brine (1×). The organic layer was driedover Na₂SO₄, filtered and evaporated under reduced pressure. The crudeproduct was purified by column chromatography on silica gel (0-10%methanol in dichloromethane) to yield1-(2,3-dihydrobenzofuran-5-yl)-N-(4,5-dimethyl-6-(2-oxo-1,2-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamideas a white solid (82 mg, 81%). ESI-MS m/z calc. 401.5, found 402.5(M+1)⁺. Retention time 1.18 minutes.

BD.1-(2,3-Dihydrobenzofuran-5-yl)-N-(6′-methoxy-3,4-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

ToN-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide(100 mg, 0.29 mmol), 6-methoxypyridin-3-ylboronic acid (67 mg, 0.44mmol) and tetrakis(triphenylphosphine)palladium (0) (34 mg, 0.029 mmol)in 1,2-dimethoxyethane (3.0 mL), 2 M Na₂CO₃ (438 μL, 0.87 mmol) wasadded. The reaction mixture was stirred and heated at 80° C. for 15hours under N₂ atmosphere. The reaction mixture was diluted with ethylacetate (5 mL), dried over Na₂SO₄, filtered and evaporated under reducedpressure. The crude product was purified by column chromatography onsilica gel (0-30% ethyl acetate in hexane) to yield1-(2,3-dihydrobenzofuran-5-yl)-N-(6′-methoxy-3,4-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamideas a white solid (105 mg, 86.6%). ESI-MS m/z calc. 415.5, found 416.5(M+1)⁺. Retention time 1.66 minutes.

BE.1-(2,3-Dihydrobenzofuran-5-yl)-N-(4,5-dimethyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

To a suspension of1-(2,3-dihydrobenzofuran-5-yl)-N-(6′-methoxy-3,4-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(100 mg, 0.24 mmol) in CH₃CN (4.75 mL) was added TMSI (68.4 μL, 0.48mmol) drop wise. The reaction was stirred at 55° C. After 65 minutes,mainly starting material and some product observed. Two more equivalentsof TMSI were added and the heating at 55° C. was continued for 3 hours20 minutes. The reaction was allowed to cool down to room temperature.Methanol (1.0 mL) was added followed by ethyl acetate (6 mL). Theorganic layer was washed with NaHSO₃ (2×: until the yellow colourdisappeared), and brine (1×). The organic layer was dried over Na₂SO₄,filtered and evaporated under reduced pressure. The crude product waspurified by column chromatography on silica gel (0-10% methanol indichloromethane) to yield1-(2,3-dihydrobenzofuran-5-yl)-N-(4,5-dimethyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamideas a white solid (60 mg, 62%). ESI-MS m/z calc. 401.5, found 402.3(M+1)⁺. Retention time 1.33 minutes.

BF.1-(2,3-Dihydrobenzofuran-5-yl)-N-(2′-methoxy-3,4-dimethyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide

ToN-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide(100 mg, 0.29 mmol), 2-methoxypyridin-4-ylboronic acid (67 mg, 0.44mmol) and tetrakis(triphenylphosphine)palladium (0) (34 mg, 0.029 mmol)in 1,2-dimethoxyethane (3.0 mL), 2 M Na₂CO₃ (438 μL, 0.87 mmol) wasadded. The reaction mixture was stirred and heated at 80° C. for 16hours under N₂ atmosphere. Product and starting material were observed.0.5 Equivalents of 2-methoxypyridin-4-ylboronic acid and 0.05equivalents of tetrakis(triphenylphosphine)palladium (0) were added andcontinued heating for 40 hours. The reaction mixture was diluted withethyl acetate (5 mL), dried over Na₂SO₄, filtered and evaporated underreduced pressure. The crude product was purified by columnchromatography on silica gel (0-30% ethyl acetate in hexane) to yield1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-3,4-dimethyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamideas a yellow solid (107 mg, 88%). ESI-MS m/z calc. 415.5, found 416.7(M+1)⁺. Retention time 1.74 minutes.

BG.1-(2,3-Dihydrobenzofuran-5-yl)-N-(4,5-dimethyl-6-(2-oxo-1,2-dihydropyridin-4-yl)pyridin-2-yl)cyclopropanecarboxamide

To a suspension of1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-3,4-dimethyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide(96 mg, 0.23 mmol) in CH₃CN (4.8 mL) was added TMSI (65.6 μL, 0.46 mmol)drop wise. The suspension became a clear solution on TMSI addition. Thereaction was stirred at 55° C. for 5 hours. The reaction was allowed tocool down to room temperature. Methanol (1.0 mL) was added followed byethyl acetate (6 mL). The organic layer was washed with NaHSO₃ (2×), andbrine (1×). The organic layer was dried over Na₂SO₄, filtered andevaporated under reduced pressure. The crude product was purified bycolumn chromatography on silica gel (0-10% methanol in dichloromethane)to yield142,3-dihydrobenzofuran-5-yl)-N-(4,5-dimethyl-6-(2-oxo-1,2-dihydropyridin-4-yl)pyridin-2-yl)cyclopropanecarboxamideas a white solid (50 mg, 54%). ESI-MS m/z calc. 401.5, found 402.5(M+1)⁺. Retention time 1.41 minutes.

BH.1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-4,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

To a mixture ofN-(6-chloro-4-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(60 mg, 0.16 mmol) and 2-methoxy-5-methylpyridin-3-ylboronic acid (41mg, 0.25 mmol) in DME (2 mL) and Na₂CO₃ (2M, 0.165 mL, 0.32 mmol) wasadded Pd(PPh₃)₄ (9.5 mg, 0.008 mmol). The mixture was heated inmicrowave oven at 120° C. for 30 min. The reaction was re-partitionedbetween EtOAc and H₂O and the aqueous layer was extracted with ethylacetate twice. The combined organic layers were washed with brine anddried over MgSO₄. After the removal of solvent, the residue was purifiedby column chromatography (0-20% EtOAc-Hexane) to yield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-4,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(72 mg, 97%). ¹H NMR (400 MHz, CDCl3) 7.98 (s, 1H), 7.96 (dd, J=0.7, 2.4Hz, 1H), 7.77 (d, J=2.3 Hz, 1H), 7.68 (s, 1H), 7.48 (d, J=9.0 Hz, 1H),7.23 (dd, J=1.7, 9.4 Hz, 2H), 7.10 (d, J=8.2 Hz, 1H), 3.96 (s, 3H), 2.40(s, 3H), 2.26 (s, 3H), 1.77-1.70 (m, 2H), 1.19-1.11 (m, 2H). Retentiontime: 2.01 min; ESI-MS m/z calc. 453.4, found 454.2 (M+H)⁺.

BI.1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-hydroxy-4,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

To a suspension of1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-4,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(70 mg, 0.15 mmol) in CH₃CN (3 mL) was added TMSI (44 uL, 0.30 mmol)dropwise at 20° C. The reaction was stirred at 50° C. for 30 min. MeOH(1.0 mL) was added and the solution was re-partitioned between EtOAc andH₂O, washed with NaHSO₃ (2×), brine, dried over MgSO₄ and evaporated todryness to yield a white solid. The crude material was further purifiedby column chromatography (0-10% MeOH-EtOAc) to yield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-hydroxy-4,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(62 mg, 91%). H NMR (400 MHz, MeOD) 7.81 (s, 2H), 7.65 (s, 1H), 7.31 (d,J=1.5 Hz, 1H), 7.25 (dd, J=1.7, 8.3 Hz, 1H), 7.17-7.14 (m, 2H), 2.29 (s,3H), 2.03 (s, 3H), 1.57 (dd, J=4.0, 7.0 Hz, 2H), 1.15 (dd, J=4.0, 7.0Hz, 2H). Retention time: 1.42 min; ESI-MS m/z calc. 439.4, found 440.5(M+H)⁺.

BG.1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,4,5′-trimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

To a mixture ofN-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(114 mg, 0.3 mmol) and 2-methoxy-5-methylpyridin-3-ylboronic acid (75mg, 0.45 mmol) in DME (3 mL) and Na₂CO₃ (2M, 0.3 mL, 0.6 mmol) was addedPd(PPh₃)₄ (17 mg, 0.015 mmol). The mixture was heated in microwave ovenat 120° C. for 30 min. The reaction was re-partitioned between EtOAc andH₂O and the aqueous layer was extracted with EtOAc twice. The combinedorganic layers were washed with brine and dried over MgSO₄. After theremoval of solvent, the residue was purified by column chromatography(0-20% EtOAc-Hexane) to yield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,4,5′-trimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(80 mg, 57%). 1H NMR (400 MHz, CDCl3) 8.02 (s, 1H), 7.99 (d, J=1.6 Hz,1H), 7.59 (s, 1H), 7.31 (d, J=2.1 Hz, 1H), 7.20-7.16 (m, 2H), 7.04 (d,J=8.1 Hz, 1H), 3.85 (s, 3H), 2.33 (s, 3H), 2.26 (s, 3H), 1.95 (s, 3H),1.73 (dd, J=3.8, 6.9 Hz, 2H), 1.14 (dd, J=3.9, 7.0 Hz, 2H). Retentiontime: 2.02 min; ESI-MS m/z calc. 467.5, found 468.2 (M+H)⁺.

BK.1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-hydroxy-3,4,5′-trimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

To a suspension of1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,4,5′-trimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(75 mg, 0.16 mmol) in CH₃CN (3 mL) was added TMSI (46 uL, 0.30 mmol)dropwise at 20° C. The reaction was stirred at 50° C. for 30 min) MeOH(1.0 mL) was added and the solution was re-partitioned between EtOAc andH₂O, washed with NaHSO₃ (2×), brine, dried over MgSO₄ and evaporated todryness to yield a white solid. The crude material was further purifiedby column chromatography (0-10% MeOH-EtOAc) to yield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-hydroxy-3,4,5′-trimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(67 mg, 92%). 1H NMR (400 MHz, MeOD) 7.89 (s, 1H), 7.31-7.27 (m, 2H),7.23-7.19 (m, 2H), 7.12 (d, J=8.3 Hz, 1H), 2.25 (s, 3H), 2.03 (s, 3H),1.97 (s, 3H), 1.56 (dd, J=3.9, 7.0 Hz, 2H), 1.13 (dd, J=3.8, 6.9 Hz,2H). Retention time: 1.52 min; ESI-MS m/z calc. 453.4, found 454.5(M+H)+.

BL.1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3,4,4′-trimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

To a mixture ofN-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(25 mg, 0.067 mmol) and 2-methoxy-4-methylpyridin-5-ylboronic acid (21mg, 0.1 mmol) in DME (0.7 mL) and Na₂CO₃ (2M, 0.065 mL, 0.13 mmol) wasadded Pd(PPh₃)₄ (4 mg, 0.003 mmol). The mixture was heated in microwaveoven at 120° C. for 30 min. The reaction was re-partitioned betweenEtOAc and H₂O and the aqueous layer was extracted with EtOAc twice. Thecombined organic layers were washed with brine and dried over MgSO₄.After the removal of solvent, the residue was purified by columnchromatography (0-20% EtOAc-Hexane) to yield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3,4,4′-trimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(20 mg, 65%). 1H NMR (400 MHz, CDCl3) 8.05 (s, 1H), 7.86 (s, 1H), 7.59(d, J=1.5 Hz, 1H), 7.21-7.16 (m, 2H), 7.04 (d, J=8.2 Hz, 1H), 6.62 (s,1H), 3.92 (s, 3H), 2.34 (s, 3H), 2.00 (s, 3H), 1.96 (s, 3H), 1.74 (dd,J=3.9, 6.9 Hz, 2H), 1.15 (dd, J=3.9, 7.0 Hz, 2H). Retention time: 2.00min; ESI-MS m/z calc. 467.5, found 468.2 (M+H)⁺.

BM.1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-hydroxy-3,4,4′-trimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

To a suspension of1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3,4,4′-trimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(17 mg, 0.036 mmol) in CH₃CN (0.7 mL) was added TMSI (10 uL, 0.072 mmol)dropwise at 20° C. The reaction was stirred at 50° C. for 30 min.Additional TMSI (10 uL, 0.072 mmol) was added and the reaction washeated at 50° C. for 2 h. Additional TMSI (10 uL, 0.072 mmol) was addedand the reaction was heated at 70° C. for 2 h. MeOH (1.0 mL) was addedand the solution was re-partitioned between EtOAc and H₂O. The organiclayer was washed with NaHSO₃ (2×), brine, dried over MgSO₄ andevaporated to dryness to yield a white solid that was further purifiedby preparative TLC (10% MeOH-EtOAc) to yield1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-hydroxy-3,4,4′-trimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(8 mg, 49%). 1H NMR (400 MHz, MeOD) 7.92 (s, 1H), 7.28 (d, J=1.6 Hz,1H), 7.22 (dd, J=1.7, 8.3 Hz, 1H), 7.14-7.10 (m, 2H), 6.36 (s, 1H), 2.27(s, 3H), 1.95 (s, 3H), 1.81 (d, J=0.6 Hz, 3H), 1.56 (dd, J=3.9, 7.0 Hz,2H), 1.14 (dd, J=3.9, 7.0 Hz, 2H). Retention time: 1.49 min; ESI-MS m/zcalc. 453.4, found 454.2 (M+H)⁺.

BN.1-(Benzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-2,3′-bipyridin-6-vyl)cyclopropanecarboxamide

1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-bromopyridin-2-yl)cyclopropanecarboxamide(36 mg, 0.10 mmol) was dissolved in 1 mL of ethanol containing 0.12 mLof a 2 M aqueous solution of potassium carbonate,2-methoxypyridin-3-ylboronic acid (18 mg, 0.12 mmol) and 6 mg ofFibre-Cat 1007. The reaction mixture was then heated to 110° C. for 10minutes in a microwave reactor. The resulting material was cooled toroom temperature, filtered, and purified by reverse-phase preparativeliquid chromatography utilizing a gradient of 0-99% acetonitrile inwater containing 0.05% trifluoroacetic acid to yield the pure product.ESI-MS m/z calc. 389.1, found 390.1 (M+1)⁺. Retention time 3.09 minutes.

BO.1-(Benzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-bromopyridin-2-yl)cyclopropanecarboxamide(36 mg, 0.10 mmol) and 6-methoxypyridin-3-ylboronic acid (19 mg, 0.12mmol) were dissolved in 1 mL of N,N-dimethylformamide (DMF) containing0.2 mL of a 2M aqueous solution of potassium carbonate potassiumcarbonate and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (Pd(dppf)Cl₂, 7.1 mg, 0.010 mmol). Theresulting solution was stirred and heated to 80° C. for 16 hours. Theresulting material was cooled to room temperature, filtered, andpurified by reverse-phase preparative liquid chromatography utilizing agradient of 0-99% acetonitrile in water containing 0.05% trifluoroaceticacid to yield the pure product. ESI-MS m/z calc. 389.1, found 390.1(M+1)⁺. Retention time 3.57 minutes

BP.1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(1-(2-(methylsulfonyl)ethyl)-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(325 mg, 0.886 mmol), tetrakis(triphenylphosphine)palladium (0) (51.20mg, 0.044 mmol), potassium carbonate (1.1 mL of 2 M, 2.21 mmol), and1-(2-(methylsulfonyl)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one(377 mg, 1.15 mmol) were combined in a scintillation vial containing1,2-dimethoxyethane (8 mL). The reaction mixture was then stirred andheated to 80 degrees C. for 16 hours. The reaction was then allowed tocool to room temperature. The layers were then separated and the organiclayer was evaporated to dryness, re-dissolved in 1 mL ofN,N-dimethylformamide, and purified by reverse-phase preparative liquidchromatography utilizing a gradient of 0-99% acetonitrile (containing0.035% trifluoroacetic acid (v/v)) in water (containing 0.05%trifluoroacetic acid (v/v)) to yield the product. The resultingtrifluoroacetic acid salt was then dissolved in a minimum ofdichloromethane (5 mL). This solution was then washed two times with asaturated aqueous solution of sodium bicarbonate, followed by two washesof a saturated aqueous solution of sodium chloride, followed by twowashes of water. The organic layer was dried over sodium sulfate andthen evaporated to dryness. The product was then further purified on 4 gof silica utilizing a gradient of 0-10% methanol in dichloromethane toyield the pure product (16.7 mg, 3.5%). ESI-MS m/z calc. 531.1, found532.1 (M+1)⁺. Retention time 1.52 minutes. ¹H NMR (400 MHz, CD₃CN) δ7.94 (d, J=8.4 Hz, 1H), 7.77 (s, 1H), 7.65 (d, J=2.3 Hz, 1H), 7.62-7.55(m, 2H), 7.36-7.32 (m, 2H), 7.22 (d, J=8.2 Hz, 1H), 6.42 (d, J=9.4 Hz,1H), 4.29 (t, J=6.7 Hz, 2H), 3.49 (t, J=6.7 Hz, 2H), 2.90 (s, 3H), 2.32(s, 3H), 1.62-1.58 (m, 2H), 1.19-1.15 (m, 2H).

BQ.N-(6-(1-(cyanomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide

N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(325.2 mg, 0.89 mmol),2-(2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-1(2H)-yl)acetonitrile(0.300 g, 1.15 mmol), tetrakis(triphenylphosphine)palladium (0) (51 mg,0.044 mmol) and potassium carbonate (1.71 g, 1.11 mL of 2 M, 2.21 mmol)were combined in a scintillation vial containing 1,2-dimethoxyethane (8mL). The reaction mixture was then stirred and heated to 80° C.overnight. The crude reaction mixture was purified by reverse-phasepreparative liquid chromatography to yield the product (25.3 mg, 6.1%)as a trifluoracetic acid salt. ESI-MS m/z calc. 464.1, found 465.1(M+1)⁺. Retention time 2.00 minutes.

BR.N-(5-Cyano-4-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide

Step a:N-(3-Cyano-6′-methoxy-4-methyl-2,3′-bipyridin-6-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide

N-(6-chloro-5-cyano-4-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(369 mg, 0.94 mmol), potassium carbonate (1.45 g, 942.0 μL of 2 M, 1.88mmol), tetrakis(triphenylphosphine)palladium (0) (54 mg, 0.047 mmol),1,2-dimethoxyethane (9 mL), and 2-methoxypyridine-5-boronic acid (230.5mg, 1.51 mmol) were combined in a 40 mL scintillation vial. The reactionmixture was heated to 80° C. for 6 hours. The reaction mixture wasallowed to cool to room temperature, the layers were separated, and thecrude material was purified on 40 g of silica gel utilizing a gradientof 0-80% ethyl acetate in hexanes to yield the pure product (0.437 g,71%). ESI-MS m/z calc. 464.1, found 465.1 (M+1)⁺. Retention time 2.08minutes.

Step b:N-(5-Cyano-4-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide

N-(3-cyano-6′-methoxy-4-methyl-2,3′-bipyridin-6-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(0.150 g, 0.323 mmol) was dissolved in acetonitrile (7.2 mL).Iodotrimethylsilane (129.3 mg, 92 μL, 0.65 mmol) was added and thereaction mixture was heated to 55° C. for 5 hours. The crude reactionmixture was then evaporated to dryness, re-dissolved in a minimum ofdichloromethane and purified on 12 g of silica gel utilizing a gradientof 0-100% ethyl acetate in hexanes (0.125 g, 86%). ESI-MS m/z calc.450.1, found 451.1 (M+1)⁺. Retention time 1.60 minutes. ¹H NMR (400 MHz,CDCl₃) 8.17 (s, 1H), 8.07-8.03 (m, 2H), 7.82 (s, 1H), 7.26 (dd, J=1.7,8.2 Hz, 1H), 7.19-7.16 (m, 2H), 6.69 (d, J=10.4 Hz, 1H), 2.58 (s, 3H),1.80-1.75 (m, 2H), 1.27-1.22 (m, 2H).

BS.1-(2,3-Dihydrobenzofuran-5-yl)-N-(4-methyl-6-(2-oxo-1,2-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

Step a:1-(2,3-Dihydrobenzofuran-5-yl)-N-(2′-methoxy-4-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

ToN-(6-chloro-4-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide(150 mg, 0.46 mmol) in 1,2-dimethoxyethane (4 mL) was added2-methoxypyridin-3-ylboronic acid (84 mg, 0.55 mmol),tetrakis(triphenylphosphine)palladium (0) (53 mg, 0.046 mmol), and 2 MNa₂CO₃ (680 μL, 1.4 mmol). The reaction mixture was irradiated in themicrowave at 120° C. for 20 minutes. The reaction mixture was evaporatedto dryness and the residue was purified by silica gel chromatographyeluting with (0-20% ethyl acetate/hexanes) to yield1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-4-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(69 mg, 38%).

Step b:1-(2,3-Dihydrobenzofuran-5-yl)-N-(4-methyl-6-(2-oxo-1,2-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

To a suspension of1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-4-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(69 mg, 0.17 mmol) in CH₃CN (2.5 mL) was added TMSI (49 uL, 0.34 mmol)dropwise at 20° C. The reaction was stirred at 50° C. for 30 min. MeOH(1.0 mL) was added and the solution was evaporated to dryness. Theresidue was re-dissolved in DCM-EtOAc (1:3) before it was washed withNaHSO₃ (2×) and brine. The organics were dried over MgSO₄ and evaporatedto dryness. The crude material was purified by column chromatography(0-10% MeOH-EtOAc) to yield1-(2,3-dihydrobenzofuran-5-yl)-N-(4-methyl-6-(2-oxo-1,2-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide.ESI-MS m/z calc. 387.2, found 388.1 (M+1)⁺. Retention time 1.38 minutes.

BT.1-(2,3-Dihydrobenzofuran-5-yl)-N-(4-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

Step a:1-(2,3-Dihydrobenzofuran-5-yl)-N-(6′-methoxy-4-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

ToN-(6-chloro-4-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide(200 mg, 0.61 mmol) in 1,2-dimethoxyethane (3 mL) was added6-methoxypyridin-3-ylboronic acid (110 mg, 0.73 mmol),tetrakis(triphenylphosphine)-palladium (0) (70 mg, 0.061 mmol), and 2 MNa₂CO₃ (910 μL, 1.8 mmol). The reaction mixture was irradiated in themicrowave at 120° C. for 20 minutes. The reaction mixture was evaporatedto dryness and the residue was purified by silica gel chromatographyeluting with (0-20% ethyl acetate/hexanes) to yield1-(2,3-dihydrobenzofuran-5-yl)-N-(6′-methoxy-4-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(147 mg, 60%). ESI-MS m/z calc. 401.2, found 402.3 (M+1)⁺. Retentiontime 1.90 minutes.

Step b:1-(2,3-Dihydrobenzofuran-5-yl)-N-(4-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

To a suspension of1-(2,3-dihydrobenzofuran-5-yl)-N-(6′-methoxy-4-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(180 mg, 0.45 mmol) in CH₃CN (7 mL) was added TMSI (130 uL, 0.90 mmol)dropwise at 20° C. The reaction was stirred at 50° C. for 30 min. MeOH(1.0 mL) was added and the solution was evaporated to dryness. Theresidue was re-dissolved in DCM-EtOAc (1:3) before it was washed withNaHSO₃ (2×) and brine. The organics were dried over MgSO₄ and evaporatedto dryness. The crude material was purified by HPLC to yield1-(2,3-dihydrobenzofuran-5-yl)-N-(4-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide.ESI-MS m/z calc. 387.2, found 388.1 (M+1)⁺. Retention time 1.35 minutes.

BU.1-(2,3-Dihydrobenzofuran-5-yl)-N-(4-methyl-6-(2-oxo-1,2-dihydropyridin-4-yl)pyridin-2-yl)cyclopropanecarboxamide

Step a:1-(2,3-Dihydrobenzofuran-5-yl)-N-(2′-methoxy-4-methyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide

ToN-(6-chloro-4-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide(150 mg, 0.46 mmol) in 1,2-dimethoxyethane (4 mL) was added2-methoxypyridin-4-ylboronic acid (84 mg, 0.55 mmol),tetrakis(triphenylphosphine)palladium (0) (53 mg, 0.046 mmol), and 2 MNa₂CO₃ (680 μL, 1.4 mmol). The reaction mixture was irradiated in themicrowave at 120° C. for 20 minutes. The reaction mixture was evaporatedto dryness and the residue was purified by silica gel chromatographyeluting with (0-20% ethyl acetate/hexanes) to yield1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-4-methyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide(76 mg, 42%). ESI-MS m/z calc. 401.2, found 402.3 (M+1)⁺. Retention time1.88 minutes.

Step b:1-(2,3-Dihydrobenzofuran-5-yl)-N-(4-methyl-6-(2-oxo-1,2-dihydropyridin-4-yl)pyridin-2-yl)cyclopropanecarboxamide

To a suspension of1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-4-methyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide(78 mg, 0.19 mmol) in CH₃CN (3 mL) was added TMSI (55 uL, 0.39 mmol)dropwise at 20° C. The reaction was stirred at 50° C. for 30 min. MeOH(1.0 mL) was added and the solution was evaporated to dryness. Theresidue was re-dissolved in DCM-EtOAc (1:3) before it was washed withNaHSO₃ (2×) and brine. The organics were dried over MgSO₄ and evaporatedto dryness. The crude material was purified by column chromatography(0-10% MeOH-EtOAc) to yield1-(2,3-dihydrobenzofuran-5-yl)-N-(4-methyl-6-(2-oxo-1,2-dihydropyridin-4-yl)pyridin-2-yl)cyclopropanecarboxamide.ESI-MS m/z calc. 387.2, found 388.3 (M+1)⁺. Retention time 1.36 minutes.

BV.N-(5′-chloro-6′-methoxy-3-methyl-2,3′-bipyridin-6-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide

To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (73 mg, 0.2 mmol) in1,2-dimethoxyethane (2 mL) was added3-chloro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(65 mg, 0.24 mmol), tetrakis(triphenylphosphine)palladium (0) (12 mg,0.01 mmol), and 2 M sodium carbonate (0.20 mL, 0.4 mmol). The reactionmixture was heated to 80° C. in an oil bath overnight. The reactionmixture was diluted with dichloromethane (5 mL) and washed with water (5mL). The organics were dried over sodium sulfate and evaporated todryness. The crude reaction mixture was purified by silica gelchromatography (eluting with 0-100% ethyl acetate in hexanes) to yieldthe product (26 mg, 27%). ESI-MS m/z calc. 473.86, found 474.3 (M+1)⁺.Retention time 2.27 minutes.

BW.1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5′,6′-dimethoxy-3-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (73 mg, 0.2 mmol) in1,2-dimethoxyethane (2 mL) was added2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(63 mg, 0.24 mmol), tetrakis(triphenylphosphine)palladium (0) (12 mg,0.01 mmol), and 2 M sodium carbonate (0.20 mL, 0.4 mmol). The reactionmixture was irradiated in the microwave at 120° C. for twenty minutes.The reaction mixture was diluted with ethyl acetate (5 mL) and washedwith water (5 mL). The organics were dried over sodium sulfate andevaporated to dryness. The crude reaction mixture was purified by silicagel chromatography (eluting with 0-100% ethyl acetate in hexanes) toyield the product (51 mg, 55%). ESI-MS m/z calc. 469.44, found 470.5(M+1)⁺. Retention time 2.03 minutes.

BX.6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-6′-methoxy-N,N,3-trimethyl-2,3′-bipyridine-5′-carboxamide

Step a: Methyl6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-6′-methoxy-3-methyl-2,3′-bipyridine-5′-carboxylate

ToN-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(0.26 g, 0.7 mmol) in 1,2-dimethoxyethane (7 mL) was added methyl2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate(0.25 g, 0.86 mmol), tetrakis(triphenylphosphine)palladium (0) (42 mg,0.04 mmol), and 2 M sodium carbonate (0.70 mL, 1.4 mmol). The reactionmixture was irradiated in the microwave at 120° C. for twenty minutes.The reaction mixture was diluted with ethyl acetate (5 mL) and washedwith water (5 mL). The organics were dried over sodium sulfate andevaporated to dryness. The crude reaction mixture was purified by silicagel chromatography (eluting with 0-100% ethyl acetate in hexanes) toyield the product (0.29 g, 81%). ESI-MS m/z calc. 497.45, found 498.3(M+1)⁺. Retention time 2.14 minutes.

Step b:6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-6′-methoxy-3-methyl-2,3′-bipyridine-5′-carboxylicacid

To a flask containing methyl6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-6′-methoxy-3-methyl-2,3′-bipyridine-5′-carboxylate(0.22 g, 0.45 mmol) was added a mixture of 2M Lithium hydroxide (2.5 mLof 2 M, 5.0 mmol) and 1,4-dioxane (2.5 mL) and the reaction mixture wasstirred at room temperature for two hours. The reaction mixture wasevaporated and residue was suspended between dichloromethane (10 mL) and1 N hydrochloric acid (10 mL). The organics were dried over sodiumsulfate and evaporated to give the product (0.20 g, 95%). ESI-MS m/zcalc. 483.12, found 484.5 (M+1)⁺Retention time 1.85 minutes.

Step c:6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-6′-methoxy-N,N,3-trimethyl-2,3′-bipyridine-5′-carboxamide

To a solution of6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-6′-methoxy-3-methyl-2,3′-bipyridine-5′-carboxylicacid (72 mg, 0.15 mmol), dimethyl amine (10 mg, 0.23 mmol), andtriethylamine (42 μL, 0.30 mmol) in N,N-dimethylformamide (1 mL) wasadded 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (68 mg, 0.18 mmol) and the reaction mixture wasstirred at 80° C. overnight. The crude reaction mixture was purified bysilica gel chromatography (eluting with 0-100% ethyl acetate in hexanes)to yield the product (51 mg, 67%). ESI-MS m/z calc. 510.49, found 511.5(M+1)⁺. Retention time 1.81 minutes.

BY.N-(6-(1-(2-cyanamido-2-oxoethyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide

Step a: Methyl2-(5-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-2-oxopyridin-1(2H)-yl)acetate

To a flask containing1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide(0.15 g, 0.35 mmol), methyl chloroacetate (0.19 g, 1.8 mmol), andpotassium carbonate (0.5 g, 3.5 mmol) was added dichloroethane (7 mL)and the reaction mixture was heated to 100° C. in a sealed tubeovernight. The reaction was diluted with dichloromethane (15 mL) andwashed with water (10 mL). The organics were dried over sodium sulfateand evaporated to dryness. The crude reaction was purified by silica gelchromatography (eluting with 0-10% methanol in dichloromethane) to givethe product (0.13 g, 76%). ESI-MS m/z calc. 497.14, found 498.3(M+1)⁺Retention time 1.73 minutes.

Step b:2-(5-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-2-oxopyridin-1(2H)-yl)aceticacid

To a flask containing methyl2-(5-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-2-oxopyridin-1(2H)-yl)acetate(0.13 g, 0.27 mmol) was added a mixture of 2M Lithium hydroxide (1 mL of2 M, 2.0 mmol) and 1,4-dioxane (4 mL) and the reaction mixture washeated to 60° C. for 2 hrs. The reaction mixture was evaporated and theresulting residue was suspended between ethyl acetate (10 mL) and 1 Nhydrochloric acid (10 mL). The organics were dried over sodium sulfateand evaporated to give the product (0.13 g, 98%). ESI-MS m/z calc.483.12, found 484.5 (M+1)⁺Retention time 1.59 minutes.

Step c:N-(6-(1-(2-cyanamido-2-oxoethyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide

To2-(5-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-2-oxopyridin-1(2H)-yl)aceticacid (0.13 g, 0.27 mmol), cyanamide (27 μL, 0.32 mmol), andtriethylamine (75 μL, 0.54 mmol) in N,N-dimethylformamide (3 mL) wasadded 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.12 g, 0.33 mmol) and the reaction mixture wasstirred at room temperature for 1 hour. At this point the reactionmixture was filtered and purified by reverse-phase HPLC. The resultingtrifluoroacetic acid salt was dissolved in dichloromethane and washedwith a saturated sodium bicarbonate solution and 1 N Hydrochloric acid.The organics were dried over sodium sulfate and evaporated to dryness togive the product (45 mg, 31%). ESI-MS m/z calc. 507.14, found 508.4(M+1)⁺Retention time 1.63 minutes.

BZ.1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(5-fluoro-2-oxo-1,2-dihydropyridin-4-yl)-5-methylpyridin-2-yl)cyclopropanecarboxamide

Step a:1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5′-fluoro-2′-methoxy-3-methyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide

ToN-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(73 mg, 0.2 mmol) in 1,2-dimethoxyethane (2 mL) was added5-fluoro-2-methoxypyridin-4-ylboronic acid (44 mg, 0.26 mmol),tetrakis(triphenylphosphine)palladium (0) (12 mg, 0.01 mmol), and 2 Msodium carbonate (0.20 mL, 0.4 mmol). The reaction mixture wasirradiated in the microwave at 120° C. for twenty minutes. The reactionmixture was diluted with ethyl acetate (5 mL) and washed with water (5mL). The organics were dried over sodium sulfate and evaporated todryness. The crude reaction mixture was purified by silica gelchromatography (eluting with 0-100% ethyl acetate in hexanes) to yieldthe product (19 mg, 20%). ESI-MS m/z calc. 457.12, found 458.3 (M+1)⁺.Retention time 2.17 minutes.

Step b:1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(5-fluoro-2-oxo-1,2-dihydropyridin-4-yl)-5-methylpyridin-2-yl)cyclopropanecarboxamide

To1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5′-fluoro-2′-methoxy-3-methyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide(19 mg, 0.04 mmol) in chloroform (0.5 mL) was added iodotrimethylsilane(32 mg, 0.16 mmol). The reaction mixture was stirred at room temperaturefor three hours. At this point the reaction mixture was purifieddirectly by silica gel chromatography (eluting with 0-100% ethyl acetatein hexanes) to yield the product (5.1 mg, 47%). ESI-MS m/z calc. 443.38,found 444.3 (M+1)⁺. Retention time 1.63 minutes.

CA.1-(2,3-dihydrobenzofuran-5-yl)-N-(5-methyl-6-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

Step a:1-(2,3-dihydrobenzofuran-5-yl)-N-(6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

ToN-(6-chloro-5-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide(0.1 g, 0.3 mmol) in 1,2-dimethoxyethane (3 mL) was added2-methoxy-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(98 mg, 0.4 mmol), tetrakis(triphenylphosphine)palladium (0) (35 mg,0.03 mmol), and 2 M sodium carbonate (0.45 mL, 0.9 mmol) and thereaction mixture was heated to 80° C. overnight. The reaction wasdiluted with ethyl acetate (5 mL) and washed with water (5 mL). Theaqueous layer was back extracted with ethyl acetate (5 mL). The organicswere dried over sodium sulfate and evaporated. The resulting crudematerial was purified by silica gel chromatography (eluting with 0-30%ethyl acetate in hexanes) to yield the product (0.1 g, 84%). ESI-MS m/zcalc. 415.48, found 416.1 (M+1)⁺. Retention time 2.03 minutes.

Step b:1-(2,3-dihydrobenzofuran-5-yl)-N-(5-methyl-6-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

To1-(2,3-dihydrobenzofuran-5-yl)-N-(6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(98 mg, 0.24 mmol) in acetonitrile (4 mL) at 50° C. was addediodotrimethylsilane (95 mg, 0.5 mmol). The reaction was heated for onehour before being quenched with methanol (1 mL). The reaction wasdiluted with dichloromethane (15 mL) and washed with an aqueoussaturated sodium bisulfite solution (2×15 mL). The organics were driedover sodium sulfate and evaporated to dryness. The resulting white solidwas purified by silica gel chromatography (eluting with 0-10% methanolin ethyl acetate) to yield the product (74 mg, 76%) as a white solid.ESI-MS m/z calc. 401.46, found 402.5 (M+1)⁺. Retention time 1.47minutes.

CB.N-(6-(5-amino-6-oxo-1,6-dihydropyridin-3-yl)-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide

Step a:1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3-methyl-5′-nitro-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (0.11 g, 0.3 mmol) in1,2-dimethoxyethane (3 mL) was added2-methoxy-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(0.11 g, 0.39 mmol), tetrakis(triphenylphosphine)palladium (0) (17 mg,0.015 mmol), and 2 M sodium carbonate (0.3 mL, 0.6 mmol) and thereaction mixture was heated to 80° C. overnight. The crude material waspurified by silica gel chromatography (eluting with 0-35% ethyl acetatein hexanes) to yield the product (71 mg, 50%). ESI-MS m/z calc. 484.12,found 485.0 (M+1)⁺. Retention time 2.17 minutes.

Step b:N-(5′-amino-6′-methoxy-3-methyl-2,3′-bipyridin-6-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide

To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3-methyl-5′-nitro-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(71 mg, 0.15 mmol) in methanol (10 mL) was added Pd/C (15 mg, 0.015mmol) The reaction was stirred at room temperature under a balloon ofhydrogen for one hour before being filtered and evaporated to yield theproduct (53 mg, 77%). ESI-MS m/z calc. 454.15, found 455.1 (M+1)⁺.Retention time 1.75 minutes.

Step c:N-(6-(5-amino-6-oxo-1,6-dihydropyridin-3-yl)-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide

ToN-(5′-amino-6′-methoxy-3-methyl-2,3′-bipyridin-6-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(53 mg, 0.1166 mmol) in 1,4-dioxane (2 mL) was added 4M aq hydrochloricacid (0.5 mL, 2.0 mmol) and the reaction mixture was heated to 90° C.After one hour the reaction was quenched with triethlyamine (0.5 mL).The reaction mixture was evaporated to dryness and the residue wasdissolved in N,N-dimethylformamide (2 mL) and purified by reverse phaseHPLC. The fractions from the HPLC purification were neutralized withsaturated sodium bicarbonate and extracted with ethyl acetate (3×10 mL).The organics were dried over sodium sulfate and evaporated to yield theproduct (26 mg, 48%). ESI-MS m/z calc. 440.4, found 441.3 (M+1)⁺.Retention time 1.39 minutes.

CC.1-(2,3-dihydrobenzofuran-5-yl)-N-(5-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

Step a:1-(2,3-dihydrobenzofuran-5-yl)-N-(6′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

ToN-(6-chloro-5-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide(95 mg, 0.3 mmol) in 1,2-dimethoxyethane (3 mL) was added6-methoxypyridin-3-ylboronic acid (66 mg, 0.4 mmol),tetrakis(triphenylphosphine)palladium (0) (33 mg, 0.03 mmol), and 2 Msodium carbonate (0.45 mL, 0.9 mmol). The reaction mixture wasirradiated in the microwave at 120° C. for twenty minutes. The reactionmixture was diluted with ethyl acetate (5 mL) and washed with water (5mL). The organics were dried over sodium sulfate and evaporated todryness. The crude reaction mixture was purified by silica gelchromatography (eluting with 0-50% ethyl acetate in hexanes) to yieldthe product (72 mg, 62%). ESI-MS m/z calc. 401.17, found 402.5 (M+1)⁺.Retention time 1.86 minutes.

Step b:1-(2,3-dihydrobenzofuran-5-yl)-N-(5-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

To1-(2,3-dihydrobenzofuran-5-yl)-N-(6′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(72 mg, 0.18 mmol) in 1,4-dioxane (2 mL) was added 0.5 mL of an aqueous4 M hydrochloric acid solution. The reaction mixture was heated to 90°C. for 30 minutes before being quenched with triethlyamine (0.5 mL) andevaporated to dryness. The residue was dissolved inN,N-dimethylformamide (1 mL) and purified by reverse-phase preparativeliquid chromatography. The resulting trifluoroacetic acid salt wasdissolved in dichloromethane (5 mL) and washed with a saturated sodiumbicarbonate solution (5 mL). The organics were dried over sodium sulfateand evaporated to dryness to yield the product (30 mg, 44%) ESI-MS m/zcalc. 387.43, found 388.3 (M+1)⁺. Retention time 1.39 minutes. ¹H NMR(400 MHz, DMSO-d6) δ 11.75 (s, 1H), 8.18 (s, 1H), 7.89 (d, J=8.3 Hz,1H), 7.67 (d, J=8.4 Hz, 1H), 7.61-7.58 (m, 1H), 7.51 (m, 1H), 7.37 (m,1H), 7.26-7.23 (m, 1H), 6.81 (d, J=8.2 Hz, 1H), 6.36 (d, J=9.5 Hz, 1H),4.55 (t, J=8.7 Hz, 2H), 3.19 (t, J=8.7 Hz, 2H), 2.27 (s, 3H), 1.49-1.46(m, 2H), 1.11-1.09 (m, 2H).

CC.1-(2,3-Dihydrobenzofuran-5-yl)-N-(5-methyl-6-(2-oxo-1,2-dihydropyridin-4-yl)pyridin-2-yl)cyclopropanecarboxamide

Step a:1-(2,3-Dihydrobenzofuran-5-yl)-N-(2′-methoxy-3-methyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide

ToN-(6-chloro-5-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide(95 mg, 0.3 mmol) in 1,2-dimethoxyethane (3 mL) was added2-methoxypyridin-4-ylboronic acid (66 mg, 0.4 mmol),tetrakis(triphenylphosphine)palladium (0) (33 mg, 0.03 mmol), and 2 Msodium carbonate (0.45 mL, 0.9 mmol). The reaction mixture wasirradiated in the microwave at 120° C. for twenty minutes. The reactionmixture was diluted with ethyl acetate (5 mL) and washed with water (5mL). The organics were dried over sodium sulfate and evaporated todryness. The crude reaction mixture was purified by silica gelchromatography eluting with (0-50% ethyl acetate/hexanes) to yield theproduct (42 mg, 34%). ESI-MS m/z calc. 401.17, found 402.5 (M+1)⁺.Retention time 1.88 minutes.

Step b:1-(2,3-Dihydrobenzofuran-5-yl)-N-(5-methyl-6-(2-oxo-1,2-dihydropyridin-4-yl)pyridin-2-yl)cyclopropanecarboxamide

To1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-3-methyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide(42 mg, 0.1 mmol) in chloroform (2 mL) was added iodotrimethylsilane (63mg, 0.3 mmol). The reaction mixture was heated to 60° C. for one hour.The reaction was evaporated to dryness and the residue was dissolved inN,N-dimethylformamide (1 mL) and purified by reverse-phase preparativeliquid chromatography. The resulting trifluoroacetic acid salt wasdissolved in dichloromethane (5 mL) and washed with a saturated sodiumbicarbonate solution (5 mL). The organics were dried over sodium sulfateand evaporated to dryness to yield the product (14 mg, 36%) ESI-MS m/zcalc. 387.43, found 388.5 (M+1)⁺. Retention time 1.41 minutes. ¹H NMR(400 MHz, DMSO-d6) δ 11.66 (s, 1H), 8.19 (s, 1H), 7.99 (d, J=8.4 Hz,1H), 7.73 (d, J=8.5 Hz, 1H), 7.40-7.37 (m, 2H), 7.26-7.24 (m, 1H), 6.80(d, J=8.2 Hz, 1H), 6.28 (m, 1H), 6.18-6.15 (m, 1H), 4.55 (t, J=8.7 Hz,2H), 3.19 (t, J=8.6 Hz, 2H), 2.22 (s, 3H), 1.49-1.47 (m, 2H), 1.11-1.09(m, 2H)

CD.(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(1-(2,3-dihydroxypropyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-methylpyridin-2-yl)cyclopropanecarboxamide

To1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide(0.15 g, 0.35 mmol), (S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane(0.27 g, 1.8 mmol), and potassium carbonate (0.5 g, 3.5 mmol) was addedN,N-dimethylformamide and the reaction mixture was heated to 100° C.overnight. The reaction was diluted with dichloromethane (20 mL) andwashed with 1N hydrochloric acid (10 mL) and a saturated aqueous sodiumbicarbonate solution (10 mL). The organics were dried over sodiumsulfate and evaporated. The crude residue was purified by silica gelchromatography (eluting with 0-10% methanol in dichloromethane) to yieldthe product (47 mg, 27%). ESI-MS m/z calc. 499.16, found 500.2 (M+1)⁺.Retention time 1.53 minutes.

CE. Ethyl2-(5-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-2-oxopyridin-1(2H)-yl)ethylcarbamate

Step a:N-(6-(1-(2-aminoethyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide

To a flask containing1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide(0.13 g, 0.3 mmol), ten-butyl 2-bromoethylcarbamate (0.35 g, 1.6 mmol),and potassium carbonate (0.5 g, 3.1 mmol) was addedN,N-dimethylformamide (5 mL) and the reaction mixture was heated to 100°C. for 2 hours. The reaction was purified by reverse-phase preparativeliquid chromatography to give the product (24 mg, 17%). ESI-MS m/z calc.468.16, found 469.5 (M+1)⁺Retention time 1.37 minutes.

Step b: Ethyl2-(5-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-2-oxopyridin-1(2H)-yl)ethylcarbamate

To a flask containingN-(6-(1-(2-aminoethyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(36 mg, 0.08 mmol), ethyl chloroformate (10 mg, 0.09 mmol), andtriethylamine (32 μL, 0.23 mmol) was added N,N-dimethyl formamide (1 mL)and the reaction mixture was stirred at room temperature overnight. Thereaction mixture was filtered and purified by reverse-phase preparativeliquid chromatography to give the product (11 mg, 25%). ESI-MS m/z calc.540.18, found 541.7 (M+1)⁺Retention time 1.72 minutes.

CF.1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)-5-methylpyridin-2-yl)cyclopropanecarboxamide

Step a:1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5′-fluoro-2′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

ToN-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(0.1 g, 0.3 mmol) in 1,2-dimethoxyethane (3 mL) was added5-fluoro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(0.1 g, 0.39 mmol), tetrakis(triphenylphosphine)palladium (0) (17 mg,0.015 mmol), and 2 M sodium carbonate (0.3 mL, 0.6 mmol) and thereaction mixture was heated to 80° C. overnight. The crude material waspurified by silica gel chromatography (eluting with 0-35% ethyl acetatein hexanes) to yield the product (42 mg, 31%). ESI-MS m/z calc. 457.4,found 458.3 (M+1)⁺. Retention time 2.20 minutes.

Step b:1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)-5-methylpyridin-2-yl)cyclopropanecarboxamide

To1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5′-fluoro-2′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(42 mg, 0.09 mmol) in chloroform (1 mL) was added iodotrimethylsilane(55 mg, 0.3 mmol). The reaction mixture was stirred at room temperaturefor three hours. At this point the reaction mixture was purifieddirectly by silica gel chromatography (eluting with 0-100% ethyl acetatein hexanes) to yield the product (19 mg, 47%). ESI-MS m/z calc. 443.38,found 443.96 (M+1)⁺. Retention time 1.56 minutes.

CG.1-(2,3-dihydrobenzofuran-5-yl)-N-(5-methyl-6-(5-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

Step a:1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

ToN-(6-chloro-5-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide(0.1 g, 0.3 mmol) in 1,2-dimethoxyethane (3 mL) was added2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(98 mg, 0.4 mmol), tetrakis(triphenylphosphine)palladium (0) (35 mg,0.03 mmol), and 2 M sodium carbonate (0.45 mL, 0.9 mmol) and thereaction mixture was heated to 80° C. overnight. The reaction wasdiluted with ethyl acetate (5 mL) and washed with water (5 mL). Theaqueous layer was back extracted with ethyl acetate (5 mL). The organicswere dried over sodium sulfate and evaporated. The resulting crudematerial was purified by silica gel chromatography (eluting with 0-30%ethyl acetate in hexanes) to yield the product (95 mg, 76%). ESI-MS m/zcalc. 415.48, found 416.1 (M+1)⁺. Retention time 1.92 minutes.

Step b:1-(2,3-dihydrobenzofuran-5-yl)-N-(5-methyl-6-(5-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

To1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(90 mg, 0.2 mmol) in acetonitrile (4 mL) at 50° C. was addediodotrimethylsilane (87 mg, 0.4 mmol). The reaction was heated for onehour before being quenched with methanol (1 mL). The reaction wasdiluted with dichloromethane (15 mL) and washed with an aqueoussaturated sodium bisulfite solution (2×15 mL). The organics were driedover sodium sulfate and evaporated to dryness. The resulting white solidwas purified by silica gel chromatography (eluting with 0-10% methanolin ethyl acetate) to yield the product (49 mg, 55%) as a white solid.ESI-MS m/z calc. 401.46, found 402.5 (M+1)⁺. Retention time 1.32minutes.

CH.1-(2,3-dihydrobenzofuran-5-yl)-N-(5-methyl-6-(2-oxo-1,2-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

Step a:1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

ToN-(6-chloro-5-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide(95 mg, 0.3 mmol) in 1,2-dimethoxyethane (3 mL) was added2-methoxypyridin-3-ylboronic acid (66 mg, 0.4 mmol),tetrakis(triphenylphosphine)palladium (0) (33 mg, 0.03 mmol), and 2 Msodium carbonate (0.45 mL, 0.9 mmol). The reaction mixture wasirradiated in the microwave at 120° C. for twenty minutes. The reactionmixture was diluted with ethyl acetate (5 mL) and washed with water (5mL). The organics were dried over sodium sulfate and evaporated todryness. The crude reaction mixture was purified by silica gelchromatography (eluting with 0-50% ethyl acetate in hexanes) to yieldthe product (87 mg, 75%). ESI-MS m/z calc. 401.17, found 402.1 (M+1)⁺.Retention time 1.79 minutes.

Step b:1-(2,3-dihydrobenzofuran-5-yl)-N-(5-methyl-6-(2-oxo-1,2-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

To1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(87 mg, 0.2 mmol) in 1,4-dioxane (1 mL) was added 0.5 mL of an aqueous 4M hydrochloric acid solution. The reaction mixture was heated to 90° C.for 30 minutes before being quenched with triethlyamine (0.5 mL) andevaporated to dryness. The residue was dissolved inN,N-dimethylformamide (1 mL) and purified by reverse-phase preparativeliquid chromatography. The resulting trifluoroacetic acid salt wasdissolved in dichloromethane (5 mL) and washed with a saturated sodiumbicarbonate solution. The organics were dried over sodium sulfate andevaporated to dryness to yield the product (27 mg, 32%) ESI-MS m/z calc.387.43, found 388.5 (M+1)⁺. Retention time 1.23 minutes. ¹H NMR (400MHz, DMSO-d6) δ 11.81 (s, 1H), 8.02 (s, 1H), 7.94 (d, J=8.3 Hz, 1H),7.62 (d, J=8.4 Hz, 1H), 7.45 (m, 1H), 7.37-7.35 (m, 2H), 7.24 (m, 1H),6.80 (d, J=8.2 Hz, 1H), 6.24 (m, 1H), 4.54 (t, J=8.7 Hz, 2H), 3.19 (t,J=8.7 Hz, 2H), 2.07 (s, 3H), 1.50-1.47 (m, 2H), 1.11-1.08 (m, 2H).

CI.N-(6-(5-chloro-2-oxo-1,2-dihydropyridin-3-yl)-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide

Step a:N-(5′-chloro-2′-methoxy-3-methyl-2,3′-bipyridin-6-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide

To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (0.11 g, 0.3 mmol) in1,2-dimethoxyethane (3 mL) was added5-chloro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(0.11 g, 0.39 mmol), tetrakis(triphenylphosphine)palladium (0) (17 mg,0.015 mmol), and 2 M sodium carbonate (0.3 mL, 0.6 mmol) and thereaction mixture was heated to 80° C. overnight. The crude material waspurified by silica gel chromatography (eluting with 0-35% ethyl acetatein hexanes) to yield the product (55 mg, 39%). ESI-MS m/z calc. 473.1,found 474.0 (M+1)⁺. Retention time 2.33 minutes.

Step b:N-(6-(5-chloro-2-oxo-1,2-dihydropyridin-3-yl)-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide

To N-(5‘-chloro-2’-methoxy-3-methyl-2,3′-bipyridin-6-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(55 mg, 0.12 mmol) in chloroform (1 mL) was added iodotrimethylsilane(70 mg, 0.35 mmol). The reaction mixture was stirred at room temperatureovernight. At this point the reaction mixture was purified directly bysilica gel chromatography (eluting with a gradient of 0-5% methanol indichloromethane) to yield the product (24 mg, 41%). ESI-MS m/z calc.459.08, found 459.95 (MW+1)⁺. Retention time 1.62 minutes.

CJ.N-(6-(3-chloro-2-oxo-1,2-dihydropyridin-4-yl)-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide

Step a:N-(3′-chloro-2′-methoxy-3-methyl-2,4′-bipyridin-6-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide

To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (0.11 g, 0.3 mmol) in1,2-dimethoxyethane (3 mL) was added3-chloro-2-methoxypyridin-4-ylboronic acid (73 mg, 0.39 mmol),tetrakis(triphenylphosphine)-palladium (0) (17 mg, 0.015 mmol), and 2 Msodium carbonate (0.3 mL, 0.6 mmol) and the reaction mixture was heatedto 80° C. overnight. The crude material was purified by silica gelchromatography (eluting with 0-20% ethyl acetate in hexanes) to yieldthe product (72 mg, 50%). ESI-MS m/z calc. 473.10, found 474.3 (M+1)⁺.Retention time 2.19 minutes.

Step b:N-(6-(3-chloro-2-oxo-1,2-dihydropyridin-4-yl)-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide

ToN-(3′-chloro-2′-methoxy-3-methyl-2,4′-bipyridin-6-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(71 mg, 0.15 mmol) in chloroform (2 mL) was added iodotrimethylsilane(90 mg, 0.45 mmol). The reaction mixture was stirred at room temperaturefor six hours. The reaction mixture was evaporated to dryness andpurified by reverse phase preparative liquid chromatography to yield theproduct as a trifluoroacetic acid salt. The salt was dissolved indichloromethane (5 mL) and washed with a saturated sodium bicarbonatesolution (2×5 mL). The organics were dried over sodium sulfate andevaporated to yield the product (23 mg, 33%). ESI-MS m/z calc. 459.08,found 460.3 (M+1)⁺. Retention time 1.11 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 12.26 (s, 1H), 9.11 (s, 1H), 7.97 (d, J=8.5 Hz, 1H), 7.75 (d,J=8.6 Hz, 1H), 7.55 (m, 1H), 7.44 (d, J=6.6 Hz, 1H), 7.40-7.38 (m, 1H),7.35-7.32 (m, 1H), 6.11 (d, J=6.6 Hz, 1H), 2.06 (s, 3H), 1.51-1.50 (m,2H), 1.17-1.15 (m, 2H).

CK.1-(2,3-dihydrobenzofuran-6-yl)-N-(5-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

Step a:1-(2,3-dihydrobenzofuran-6-yl)-N-(2′-methoxy-3-methyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide

A mixture ofN-(6-chloro-5-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-6-yl)cyclopropanecarboxamide(50.0 mg, 0.15 mmol), 2-methoxypyridine-5-boronic acid (23.26 mg, 0.15mmol), and tetrakis(triphenylphosphine)palladium (0) (9.0 mg, 0.0076mmol) in 1,2-dimethoxyethane (1.5 mL) and 2 M Na₂CO₃ (0.3 mL) wasstirred at 80° C. for 16 hours under N₂ atmosphere. The reaction mixturewas diluted with ethyl acetate (5 mL), dried over Na₂SO₄, filtered andevaporated under reduced pressure. The crude product was purified bycolumn chromatography on silica gel (0-30% ethyl acetate in hexane) toyield 30 mg (49%) of142,3-dihydrobenzofuran-6-yl)-N-(2′-methoxy-3-methyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide.ESI-MS m/z calc. 401.2, found 402.0 (M+1)⁺. Retention time 1.83 minutes.

Step b:1-(2,3-dihydrobenzofuran-6-yl)-N-(5-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

To a slurry of1-(2,3-dihydrobenzofuran-6-yl)-N-(2′-methoxy-3-methyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide(25 mg, 0.062 mmol) in AcCN (1.5 mL) was added TMS-I (35.45 μL, 0.24mmol) and stirred at 55° C. for 7 h. The reaction was diluted withmethanol (1.0 mL) and stirred at room temperature for 2 h. The resultingmixture was concentrated under vacuum, and taken into ethyl acetate (10mL. The organic solution washed with sodium bisulphate (2×2 ml) water(2×3 mL), dried over sodium sulphate and concentrated under vacuum. Thesolid was stirred with methanol (1.0 mL) at 40° C. for 10 min andcollected by filtration, washed with methanol (1.0 mL) and dried undervacuum to yield 18.0 mg (74%) of the desired product. ESI-MS m/z calc.387.4, found 388.2 (M+1)⁺. Retention time 1.32 minutes.

CL.1-(2,3-dihydrobenzofuran-6-yl)-N-(4-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

Step a:1-(2,3-Dihydrobenzofuran-6-yl)-N-(6′-methoxy-4-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

A mixture ofN-(6-chloro-4-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-6-yl)cyclopropanecarboxamide(50.0 mg, 0.15 mmol), 2-methoxypyridine-5-boronic acid (23.0 mg, 0.15mmol), and tetrakis(triphenylphosphine)palladium (0) (8.8 mg, 0.0076mmol) in 1,2-dimethoxyethane (1.0 mL) and 2 M Na₂CO₃ (0.2 mL) wasstirred at 80° C. for 16 hours under N₂ atmosphere. The reaction mixturewas diluted with ethyl acetate (5 mL), dried over Na₂SO₄, filtered andevaporated under reduced pressure. The crude product was purified bycolumn chromatography on silica gel (0-30% ethyl acetate in hexane) toyield 20 mg (32%) of1-(2,3-dihydrobenzofuran-6-yl)-N-(6′-methoxy-4-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide.ESI-MS m/z calc. 401.2, found 402.0 (M+1)⁺. Retention time 1.94 minutes.

Step b:1-(2,3-dihydrobenzofuran-6-yl)-N-(4-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

To a slurry of1-(2,3-dihydrobenzofuran-6-yl)-N-(6′-methoxy-4-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(20 mg, 0.049 mmol) in acetonitrile (1.5 mL) was added TMS-I (28.4 μL,0.19 mmol) and the mixture was stirred at 55° C. for 7 h. The reactionwas diluted with methanol (1.0 mL) and stirred at room temperature for 2h. The resulting mixture was concentrated under vacuum, and taken intoethyl acetate (10 mL). The organic solution was washed with sodiumbisulphate (2×2 ml), water (2×3 mL), dried over sodium sulphate andconcentrated under vacuum. The solid was stirred with methanol (1.0 mL)at 40° C. for 10 min and collected by filtration, washed with methanol(1.0 mL) and dried under vacuum to yield the product (8.0 mg, 41%).ESI-MS m/z calc. 387.4, found 388.2 (M+1)⁺. Retention time 1.44 minutes.

CM.1-(4-chlorophenyl)-N-(5-methyl-6-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

Step a:1-(4-chlorophenyl)-N-(5-methyl-6-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

To a solution of 1-(4-chlorophenyl)cyclopropanecarboxylic acid (39.3 mg,0.2 mmol) in dichloromethane (2 mL) was added thionyl chloride (43.8 μL,0.6 mmol) followed by DMF (1 drop) and the reaction was stirred at roomtemperature for 30 minutes and then the solvent was removed. Toluene(˜1mL) was added, mixed with the residue and then removed byevaporation. The residue was then dissolved in dichloromethane (1 mL)and a solution of 6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-amine (46mg, 0.2 mmol) and triethyl amine (83.6 μL, 0.60 mmol) in dichloromethane(1 mL) was added. The reaction was stirred at room temperature for 12hors. The reaction was then concentrated. The residue was dissolved inDMSO and purified by reverse phase HPLC (10-99% acetonitrile/water) toyield 62 mg of the product. ESI-MS m/z calc. 407.1, found 408.2 (M+1)⁺.Retention time 2.07 minutes.

Step b:1-(4-chlorophenyl)-N-(5-methyl-6-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

To a solution of1-(4-chlorophenyl)-N-(5-methyl-6-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide(62 mg, 0.15 mmol) in acetonitrile (3 mL) was added TMS-Iodide (86.6 μL,0.61 mmol). The reaction was stirred at 50° C. for 2 hours. The reactionsolution was diluted with dichloromethane and washed with saturatedNaHSO3 (2×), brine, dried over MgSO4 and concentrated. The crude productwas dissolved in DMSO (2 mL) and purified by HPLC ((10-99%acetonitrile/water). ESI-MS m/z calc. 393.1, found 394.3 (M+1)⁺.Retention time 1.55 minutes. 1H NMR (400.0 MHz, DMSO-d6) d 8.87 (s, 1H),7.85 (d, J=8.3 Hz, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.51-7.44 (m, 5H), 7.40(d, J=2.4 Hz, 1H), 2.28 (s, 3H), 2.00 (s, 3H), 1.51-1.49 (m, 2H) and1.16-1.13 (m, 2H) ppm

CN.1-(3-chloro-4-methoxyphenyl)-N-(5-methyl-6-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

Step a:1-(3-chloro-4-methoxyphenyl)-N-(6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

To a solution of 1-(3-chloro-4-methoxyphenyl)cyclopropanecarboxylic acid(45.3 mg, 0.2 mmol) in dichloromethane (2 mL) was added thionyl chloride(43.8 μL, 0.60 mmol) followed by DMF (1 drop) and the reaction wasstirred at room temperature for 30 minutes and then the solvent wasevaporated. Toluene (˜1mL) was added and mixed with the residue and thenevaporated. The residue was then dissolved in dichloromethane (1 mL) anda solution of 6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-amine (45.9 mg,0.20 mmol) and Et₃N (83.6 μL, 0.60 mmol) in dichloromethane (1 mL) wasadded. The reaction was stirred at room temperature for 12 hours andthen the reaction was then concentrated. The residue was dissolved inDMSO and purified by HPLC (10-99% acetonitrilein water) to yield 44 mgof the product. ESI-MS m/z calc. 437.1, found 438.1 (M+1)⁺. Retentiontime 2.10 minutes.

Step b:1-(3-Chloro-4-methoxyphenyl)-N-(5-methyl-6-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

To a solution of1-(3-chloro-4-methoxyphenyl)-N-(6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(44 mg, 0.10 mmol) in acetonitrile (2 mL) was added TMS-Iodide (57.2 μL,0.40 mmol). The reaction was stirred at 50° C. for 20 min. The reactionsolution was diluted with dichloromethane and washed with saturatedNaHSO₃ (2×), brine, dried over MgSO₄ and concentrated. The crude productwas dissolved in DMSO (1 mL) and purified by reverse phase HPLC (10-99%CH₃CN in water). ESI-MS m/z calc. 423.1, found 424.3 (M+1)⁺. Retentiontime 1.52 minutes.

CO.1-(1,3-dihydroisobenzofuran-5-yl)-N-(5-methyl-6-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

Step a:1-(1,3-Dihydroisobenzofuran-5-yl)-N-(6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

To a solution of 1-(1,3-dihydroisobenzofuran-5-yl)cyclopropanecarboxylicacid (40.8 mg, 0.2 mmol) in dichloromethane (2 mL) was added thionylchloride (43.8 μL, 0.60 mmol) followed by DMF (1 drop) and the reactionwas stirred at room temperature for 30 minutes and then the solvent wasevaporated. Toluene (˜1mL) was added and mixed with the residue and thenremoved by rotovap. The residue was then dissolved in dichloromethane (1mL) and a solution of 6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-amine(45.8 mg, 0.20 mmol) and Et₃N (83.6 μL, 0.60 mmol) in dichloromethane (1mL) was added. The reaction was stirred at room temperature for 12hours. The reaction was then concentrated. The residue was dissolved inDMSO and purified by reverse phase HPLC (10-99% CH₃CN in water) to yield40 mg of the desired product. ESI-MS m/z calc. 415.2, found 416.5(M+1)⁺. Retention time 1.87 minutes.

Step b:1-(1,3-dihydroisobenzofuran-5-yl)-N-(5-methyl-6-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

To a solution of1-(1,3-dihydroisobenzofuran-5-yl)-N-(6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(40 mg, 0.1 mmol) in acetonitrile (2 mL) was added TMS-Iodide (54.8 μL,0.39 mmol). The reaction was stirred at 50° C. for 20 min. The reactionsolution was diluted with CH₂Cl₂ and washed with saturated NaHSO₃ (2×),brine, dried over MgSO₄ and concentrated. The crude product wasdissolved in DMSO (1 mL) and purified by reverse phase HPLC (10-99%CH₃CN/water). ESI-MS m/z calc. 401.1, found 402.5 (M+1)⁺. Retention time1.29 minutes.

CP.1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-N-(5-methyl-6-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

Step a:1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-(6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

To a solution of1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)cyclopropanecarboxylic acid(44.04 mg, 0.2 mmol) in dichloromethane (2 mL) was added thionylchloride (14.6 μL, 0.20 mmol) followed by DMF (1 drop) and the reactionwas stirred at room temperature for 30 minutes. The solvent was removedby rotovap. Toluene (˜1mL) was added and mixed with the residue and thenremoved by rotovap. The toluene step was repeated once more and then theresidue was placed under high vacuum for 10 minutes. It was thendissolved in dichloromethane (1 mL) and a solution of6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-amine (46 mg, 0.20 mmol) andtriethylamine (83.6 μL, 0.60 mmol) in dichloromethane (1 mL) was added.The reaction was stirred at room temperature for 12 hours. The reactionwas then concentrated. The residue was dissolved in DMSO and purified byrevrese phase HPLC (10-99% CH₃CN in water) to yield 16 mg of theproduct. ESI-MS m/z calc. 431.2, found 432.5 (M+1)⁺. Retention time 1.98minutes.

Step b:1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-(5-methyl-6-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

To a solution of1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-(6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(16 mg, 0.037 mmol) in acetonitrile (1 mL) was added TMS-Iodide (21.10μL, 0.148 mmol). The reaction was stirred at 50° C. for 20 minutes. Thereaction solution was diluted with dichloromethane and washed withsaturated NaHSO₃ (2×), brine, dried over MgSO₄ and concentrated. Thecrude product was dissolved in DMSO (1 mL) and purified by reverse phaseHPLC (10-99% CH₃CN in water). ESI-MS m/z calc. 417.5, found 418.3(M+1)⁺. Retention time 1.40 minutes.

CQ.1-(3-methoxyphenyl)-N-(5-methyl-6-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamideStep a:N-(6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)-1-(3-methoxyphenyl)cyclopropanecarboxamide

1-(3-Methoxyphenyl)cyclopropanecarboxylic acid (38.4 mg, 0.2 mmol) wasdissolved in dichloromethane (2 mL) and thionyl chloride (43.8 μL, 0.60mmol) was added followed by DMF (1 drop) and the reaction was stirred atroom temperature for 30 minutes. Then the solvent was removed byevaporation, toluene (˜1mL) was added twice, mixed with the residue andremoved by evaporation and then the residue was placed under high vacuumfor 10 minutes. It was then dissolved in dichloromethane (1 mL) and asolution of 6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-amine (45.9 mg,0.20 mmol) and triethyl amine (83.6 μL, 0.60 mmol) in dichloromethane (1mL) was added. The reaction was stirred at room temperature for 12hours. The reaction was then concentrated. The residue was dissolved inDMSO and purified by reverse phase HPLC (10-99% CH₃CN in water) to yield41 mg (50% yield) of the product. ESI-MS m/z calc. 403.5, found 404.5(M+1)⁺. Retention time 2.03 minutes.

Step b:1-(3-Methoxyphenyl)-N-(5-methyl-6-(5-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

To a solution ofN-(6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)-1-(3-methoxyphenyl)cyclopropanecarboxamide(41 mg, 0.10 mmol) in acetonitrile (2 mL) was added TMS-Iodide (28.0 μL,0.20 mmol). The reaction was stirred at 50° C. for 20 min. The reactionsolution was diluted with dichloromethane and washed with saturatedNaHSO₃ (2×), brine, dried over MgSO₄ and concentrated. The crude productwas dissolved in DMSO (1 mL) and purified by reverse phase HPLC (Gilson,10-99% CH₃CN in water) to yield the desired product. ESI-MS m/z calc.389.4, found 390.5 (M+1)⁺. Retention time 1.41 minutes.

CR.1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(1-(2-hydroxyethyl)-2-oxo-1,2-dihydropyridin-4-yl)-4-methylpyridin-2-yl)cyclopropanecarboxamide

A solution ofN-(6-chloro-4-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(217 mg, 409.0 μmol) in DME (4 mL) was added to a reaction tubecontaining1-(2-hydroxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one(150 mg, 409.0 μmol) and Pd(PPh₃)₄ (24 mg, 20.5 μmol). Saturated Na₂CO₃solution was added (400 μL) and the reaction was stirred at 80° C.overnight. The reaction was filtered and concentrated and purified twiceby column chromatography (first column: 0-5% MeOH—CH₂Cl₂; second column:75-100% Ethyl acetate-hexanes then 0-20% EtOH-ethyl acetate) to obtainthe product as a brown oil (12 mg) that was redissolved in DMSO andfurther purified by reverse phase HPLC (10-99% CH₃CN in water) to obtain4 mg of clean product as a white solid. ESI-MS m/z calc. 469.4, found470.5 (M+1)⁺. Retention time 1.66 minutes. H NMR (400 MHz, CD₃CN) 8.02(s, 1H), 7.87 (s, 1H), 7.47-7.43 (m, 2H), 7.39-7.35 (m, 2H), 7.26 (d,J=8.2 Hz, 1H), 6.94 (d, J=1.7 Hz, 1H), 6.69 (dd, J=1.9, 7.1 Hz, 1H),3.99 (t, J=5.2 Hz, 2H), 3.74 (q, J=5.2 Hz, 2H), 3.29 (t, J=5.6 Hz, 1H),2.39 (s, 3H), 1.62 (dd, J=3.9, 7.0 Hz, 2H), 1.20 (dd, J=4.0, 7.0 Hz,2H).

CS.1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,4-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

A solution ofN-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(38 mg, 0.1 mmol) in DME (1 mL) was added to a reaction tube containing2-methoxypyridin-3-ylboronic acid (46 mg, 0.15 mmol) and Pd(PPh₃)₄ (6mg, 0.005 mmol). Saturated Na₂CO₃ solution was added (100 μL) and thereaction was stirred at 80° C. overnight. The reaction was filtered,concentrated and purified by column chromatography (0-50% ethyl acetatein hexanes) to obtain 50 mg (55%) of a clear oil. ESI-MS m/z calc.453.4, found 454.5 (M+1)⁺. Retention times: 1.9 minutes. H NMR (400 MHz,DMSO) 8.81 (s, 1H), 8.22 (dd, J=1.9, 5.0 Hz, 1H), 7.84 (s, 1H),7.57-7.53 (m, 2H), 7.38-7.31 (m, 2H), 7.05 (dd, J=5.0, 7.2 Hz, 1H), 3.78(s, 3H), 2.29 (s, 3H), 1.89 (s, 3H), 1.50-1.47 (m, 2H), 1.16-1.13 (m,2H)

CT.1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,4-dimethyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide

A solution ofN-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(38 mg, 0.1 mmol) in DME (1 mL) was added to a reaction tube containing2-methoxypyridin-4-ylboronic acid (46 mg, 0.15 mmol) and Pd(PPh₃)₄ (6mg, 0.005 mmol). Saturated Na₂CO₃ solution was added (100 μL) and thereaction was stirred at 80° C. overnight. The reaction was filtered,concentrated and purified by column chromatography (0-50% ethyl acetatein hexanes) to obtain 40 mg (44%) of a clear oil. ESI-MS m/z calc.453.4, found 454.3 (M+1)⁺. Retention times: 2.06 minutes. H NMR (400MHz, DMSO) 8.85 (s, 1H), 8.20 (d, J=5.2 Hz, 1H), 7.86 (s, 1H), 7.54 (d,J=1.5 Hz, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.32 (dd, J=1.6, 8.3 Hz, 1H),6.97 (dd, J=1.2, 5.2 Hz, 1H), 6.77 (s, 1H), 3.87 (s, 3H), 2.31 (s, 3H),2.09 (s, 3H), 1.51-1.48 (m, 2H), 1.17-1.15 (m, 2H).

CU.1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3,4-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide

A solution ofN-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide(38 mg, 0.1 mmol) in DME (1 mL) was added to a reaction tube containing6-methoxypyridin-3-ylboronic acid (46 mg, 0.15 mmol) and Pd(PPh₃)₄ (6mg, 0.005 mmol). Saturated Na₂CO₃ solution was added (100 μL) and thereaction was stirred at 80° C. overnight. The reaction was filtered,concentrated and purified by column chromatography (0-50% ethyl acetatein hexanes) to obtain 40 mg (44%) of a clear oil. ESI-MS m/z calc.453.4, found 454.3 (M+1)⁺. Retention times: 2.06 minutes. H NMR (400MHz, DMSO) 8.76 (s, 1H), 8.19 (d, J=2.4 Hz, 1H), 7.82 (s, 1H), 7.74 (dd,J=2.4, 8.5 Hz, 1H), 7.55 (d, J=1.3 Hz, 1H), 7.40 (d, J=8.3 Hz, 1H), 7.33(dd, J=1.5, 8.3 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 3.88 (s, 3H), 2.31 (s,3H), 2.13 (s, 3H), 1.51-1.49 (m, 2H), 1.18-1.15 (m, 2H).

CV.1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(4,5-dimethyl-6-(2-oxo-1,2-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

To a solution of1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,4-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(40 mg, 0.09 mmol) in dioxane (1 mL) was added 4M HCl and the reactionwas stirred at 90° C. for 3 hours. To the mixture at room temperature,0.5 mL of triethyl amine was added and the reaction was concentratedunder reduced pressure. The crude residue was purified by columnchromatography using a gradient of ethyl acetate in hexanes (50-100%).ESI-MS m/z calc. 439.4, found 440.3 (M+1)⁺. Retention times: 1.39minutes. H NMR (400 MHz, DMSO) 8.67 (s, 1H), 7.80 (s, 1H), 7.55 (d,J=1.5 Hz, 1H), 7.44-7.32 (m, 4H), 6.23 (t, J=6.6 Hz, 1H), 2.27 (s, 3H),1.96 (s, 3H), 1.51-1.48 (m, 2H), 1.16-1.14 (m, 2H).

CW.1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(4,5-dimethyl-6-(6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl)cyclopropanecarboxamide

To a solution of1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3,4-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide(40 mg, 0.09 mmol) in dioxane (1 mL) was added 4M HCl and the reactionwas stirred at 90° C. for 3 hours. To the mixture at room temperature,0.5 mL of triethyl amine was added and the reaction was concentratedunder reduced pressure. The crude residue was purified by columnchromatography using a gradient of ethyl acetate in hexanes (50-100%).ESI-MS m/z calc. 439.4, found 440.3 (M+1)⁺. Retention times: 1.53minutes. H NMR (400 MHz, DMSO) 8.79 (s, 1H), 7.76 (s, 1H), 7.56-7.53 (m,2H), 7.44-7.32 (m, 3H), 6.35 (d, J=9.4 Hz, 1H), 2.28 (s, 3H), 2.15 (s,3H), 1.50-1.48 (m, 2H), 1.17-1.15 (m, 2H).

CX.1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-N-(4,5-dimethyl-6-(2-oxo-1,2-dihydropyridin-4-yl)pyridin-2-yl)cyclopropanecarboxamide

To a solution of1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,4-dimethyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide(20 mg, 0.044 mmol) in chloroform (1 mL) was added TMS-Iodide (25.6 μL,0.18 mmol). The reaction was stirred at 55° C. for one hour. Thereaction solution was diluted with dichloromethane and washed withsaturated NaHSO₃ (2×), brine, dried over MgSO₄ and concentrated. Thecrude product purified by reverse phase HPLC (10-99% CH₃CN in water) toyield the desired product. ESI-MS m/z calc. 439.4, found 440.5 (M+1)⁺.Retention time 1.61 minutes.

The analytical data for the compounds of Table 1 are shown below inTable 2:

TABLE 2 LC/MS LC/RT Cmpd # M + 1 min NMR (¹H) δ 1 456.5 1.44 2 390.5 1.83 440.3 2.19 4 483.3 1.58 5 440 1.79 6 440.3 1.64 H NMR (400 MHz, DMSO)11.67 (s, 1H), 8.93 (s, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.64 (d, J = 8.4Hz, 1H), 7.57- 7.48 (m, 2H), 7.41-7.39 (m, 2H), 7.43-7.31 (m, 1H), 2.27(s, 3H), 1.98 (s, 3H), 1.51-1.47 (m, 2H), 1.17-1.14 (m, 2H) 7 390.5 1.768 454.3 2.12 9 455.5 1.76 10 376.7 1.26 11 440 1.95 12 426 1.45 H NMR(400 MHz, DMSO) 11.78 (s, 1H), 8.91 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H),7.66-7.64 (m, 2H), 7.56-7.55 (m, 2H), 7.41 (d, J = 8.3 Hz, 1H), 7.34(dd, J = 1.7, 8.3 Hz, 1H), 6.36 (d, J = 9.5 Hz, 1H), 2.28 (s, 3H),1.52-1.49 (m, 2H), 1.18-1.15 (m, 2H) 13 484.5 1.62 14 440 1.41 15 440.11.94 16 498.3 1.76 H NMR (400 MHz, DMSO) 9.01 (s, 1H), 7.92 (d, J = 8.4Hz, 1H), 7.75-7.70 (m, 2H), 7.55 (d, J = 1.6 Hz, 1H), 7.40 (d, J = 8.3Hz, 1H), 7.34 (dd, J = 1.7, 8.3 Hz, 1H), 6.44 (d, J = 1.6 Hz, 1H), 6.35(dd, J = 1.9, 7.0 Hz, 1H), 4.74 (s, 2H), 3.69 (s, 3H), 2.26 (s, 3H),1.52-1.50 (m, 2H), 1.19-1.16 (m, 2H) 17 426.3 1.32 18 454 1.9 19 426.31.7 20 470.5 1.66 21 456.3 1.54 22 446.3 1.62 23 470.3 1.72 24 459.92.26 25 460.3 1.74 26 376.5 1.45 27 426.3 1.68 28 442.3 1.42 29 470.51.58 H NMR (400 MHz, DMSO-d6) 8.87 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H),7.73 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 6.9 Hz, 1H), 7.56 (d, J = 1.6 Hz,1H), 7.41 (d, J = 8.3 Hz, 1H), 7.34 (dd, J = 1.7, 8.3 Hz, 1H), 6.39 (d,J = 1.8 Hz, 1H), 6.26 (dd, J = 1.9, 6.9 Hz, 1H), 3.96 (t, J = 5.4 Hz,2H), 3.63 (t, J = 5.5 Hz, 2H), 2.26 (s, 3H), 1.52-1.50 (m, 2H),1.19-1.16 (m, 2H). 30 454 2.12 31 440.3 1.55 32 483.5 1.57 33 497.5 1.8334 469.3 1.5 35 440 1.75 36 454.3 1.97 37 440 2 38 440.3 2.21 39 4441.58 40 440.3 1.56 H NMR (400 MHz, DMSO) 11.69 (s, 1H), 8.91 (s, 1H),7.88 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 1.5 Hz,1H), 7.39 (d, J = 8.3 Hz, 1H), 7.33 (dd, J = 1.7, 8.3 Hz, 1H), 7.22 (d,J= 9.3 Hz, 1H), 6.17 (d, J = 9.3 Hz, 1H), 2.05 (s, 3H), 1.90 (s, 3H),1.51-1.48 (m, 2H), 1.17-1.14 (m, 2H) 41 440.5 1.65 H NMR (400 MHz, DMSO)8.92 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.73-7.71 (m, 2H), 7.56 (d, J =1.5 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.34 (dd, J = 1.7, 8.3 Hz, 1H),6.40 (d, J = 1.6 Hz, 1H), 6.27 (dd, J = 1.9, 6.9 Hz, 1H), 3.45 (s, 3H),2.24 (s, 3H), 1.52-1.49 (m, 2H), 1.19-1.16 (m, 2H) 42 451.3 1.7 43 458.52.25 44 426.3 1.57 45 390.5 1.84 46 426 1.33 47 484.5 1.62 H NMR (400MHz, DMSO) 8.98 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.74-7.68 (m, 2H),7.55 (d, J = 1.6 Hz, 1H), 7.41-7.32 (m, 2H), 6.43 (d, J = 1.7 Hz, 1H),6.32 (dd, J = 1.9, 7.0 Hz, 1H), 4.64 (s, 2H), 2.26 (s, 3H), 1.52-1.50(m, 2H), 1.18-1.16 (m, 2H) 48 440.3 1.91 49 390.3 2.02 50 426.3 1.67 51412.5 1.31 52 440.5 1.61 53 484.5 1.84 54 427.5 1.48 H NMR (400 MHz,DMSO) 9.37 (s, 1H), 9.02 (s, 1H), 7.55- 7.51 (m, 3H), 7.38 (d, J = 8.3Hz, 1H), 7.32 (dd, J = 1.7, 8.3 Hz, 1H), 6.30 (t, J = 6.6 Hz, 1H), 2.33(s, 3H), 1.55- 1.52 (m, 2H), 1.21-1.18 (m, 2H) 55 427.5 1.49 H NMR (400MHz, DMSO) 9.44 (s, 1H), 8.97 (s, 1H), 7.75- 7.70 (m, 2H), 7.54 (d, J =1.6 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.32 (dd, J = 1.7, 8.3 Hz, 1H),6.41 (d, J = 9.4 Hz, 1H), 2.52 (s, 3H), 1.55-1.52 (m, 2H), 1.22-1.19 (m,2H) 56 454.5 1.9 H NMR (400 MHz, DMSO) 8.81 (s, 1H), 8.22 (dd, J = 1.9,5.0 Hz, 1H), 7.84 (s, 1H), 7.57-7.53 (m, 2H), 7.38-7.31 (m, 2H), 7.05(dd, J = 5.0, 7.2 Hz, 1H), 3.78 (s, 3H), 2.29 (s, 3H), 1.89 (s, 3H),1.50-1.47 (m, 2H), 1.16-1.13 (m, 2H) 57 454.3 2.06 H NMR (400 MHz, DMSO)8.76 (s, 1H), 8.19 (d, J = 2.4 Hz, 1H), 7.82 (s, 1H), 7.74 (dd, J = 2.4,8.5 Hz, 1H), 7.55 (d, J = 1.3 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.33(dd, J = 1.5, 8.3 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 3.88 (s, 3H), 2.31(s, 3H), 2.13 (s, 3H), 1.51-1.49 (m, 2H), 1.18-1.15 (m, 2H) 58 454.32.06 H NMR (400 MHz, DMSO) 8.85 (s, 1H), 8.20 (d, J = 5.2 Hz, 1H), 7.86(s, 1H), 7.54 (d, J = 1.5 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.32 (dd, J= 1.6, 8.3 Hz, 1H), 6.97 (dd, J = 1.2, 5.2 Hz, 1H), 6.77 (s, 1H), 3.87(s, 3H), 2.31 (s, 3H), 2.09 (s, 3H), 1.51-1.48 (m, 2H), 1.17-1.15 (m,2H) 59 402.5 1.32 60 418.3 1.42 61 394.3 1.57 62 424.3 1.54 63 390.51.44 64 470.5 1.66 H NMR (400 MHz, CD3CN) 8.02 (s, 1H), 7.87 (s, 1H),7.47-7.43 (m, 2H), 7.39-7.35 (m, 2H), 7.26 (d, J = 8.2 Hz, 1H), 6.94 (d,J = 1.7 Hz, 1H), 6.69 (dd, J = 1.9, 7.1 Hz, 1H), 3.99 (t, J = 5.2 Hz,2H), 3.74 (q, J = 5.2 Hz, 2H), 3.29 (t, J = 5.6 Hz, 1H), 2.39 (s, 3H),1.62 (dd, J = 3.9, 7.0 Hz, 2H), 1.20 (dd, J = 4.0, 7.0 Hz, 2H) 65 440.31.53 H NMR (400 MHz, DMSO) 8.79 (s, 1H), 7.76 (s, 1H), 7.56- 7.53 (m,2H), 7.44-7.32 (m, 3H), 6.35 (d, J = 9.4 Hz, 1H), 2.28 (s, 3H), 2.15 (s,3H), 1.50-1.48 (m, 2H), 1.17- 1.15 (m, 2H) 66 440.3 1.39 H NMR (400 MHz,DMSO) 8.67 (s, 1H), 7.80 (s, 1H), 7.55 (d, J = 1.5 Hz, 1H), 7.44-7.32(m, 4H), 6.23 (t, J = 6.6 Hz, 1H), 2.27 (s, 3H), 1.96 (s, 3H), 1.51-1.48(m, 2H), 1.16-1.14 (m, 2H) 67 440.5 1.61 68 388.1 1.35 69 388.3 1.38 70388.3 1.36 71 474.3 2.35 72 470.5 1.97 73 511.5 1.82 74 508.5 1.6 75 4401.56 76 402.5 1.47 77 441.3 1.39 78 388.3 1.39 H NMR (400 MHz, DMSO-d6)11.75 (s, 1H), 8.18 (s, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.67 (d, J = 8.4Hz, 1H), 7.61- 7.58 (m, 1H), 7.51 (m, 1H), 7.37 (m, 1H), 7.26-7.23 (m,1H), 6.81 (d, J = 8.2 Hz, 1H), 6.36 (d, J = 9.5 Hz, 1H), 4.55 (t, J =8.7 Hz, 2H), 3.19 (t, J = 8.7 Hz, 2H), 2.27 (s, 3H), 1.49-1.46 (m, 2H),1.11-1.09 (m, 2H) 79 500.3 1.46 80 388.5 1.41 H NMR (400 MHz, DMSO-d6)11.66 (s, 1H), 8.19 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.5Hz, 1H), 7.40- 7.37 (m, 2H), 7.26-7.24 (m, 1H), 6.80 (d, J = 8.2 Hz,1H), 6.28 (m, 1H), 6.18-6.15 (m, 1H), 4.55 (t, J = 8.7 Hz, 2H), 3.19 (t,J = 8.6 Hz, 2H), 2.22 (s, 3H), 1.49-1.47 (m, 2H), 1.11-1.09 (m, 2H) 81541.7 1.69 82 443.96 1.52 83 402.5 1.32 84 388.5 1.23 H NMR (400 MHz,DMSO-d6) 11.81 (s, 1H), 8.02 (s, 1H), 7.94 (d, J = 8.3 Hz, 1H), 7.62 (d,J = 8.4 Hz, 1H), 7.45 (m, 1H), 7.37-7.35 (m, 2H), 7.24 (m, 1H), 6.80 (d,J = 8.2 Hz, 1H), 6.24 (m, 1H), 4.54 (t, J = 8.7 Hz, 2H), 3.19 (t, J =8.7 Hz, 2H), 2.07 (s, 3H), 1.50-1.47 (m, 2H), 1.11-1.08 (m, 2H) 85 459.91.69 86 460.3 1.68 H NMR (400 MHz, DMSO-d6) 12.26 (s, 1H), 9.11 (s, 1H),7.97 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.55 (m, 1H), 7.44(d, J = 6.6 Hz, 1H), 7.40-7.38 (m, 1H), 7.35- 7.32 (m, 1H), 6.11 (d, J =6.6 Hz, 1H), 2.06 (s, 3H), 1.51- 1.50 (m, 2H), 1.17-1.15 (m, 2H) 87454.2 1.96 88 468.2 2.02 89 468.2 1.94 90 454.2 1.49 91 454.5 1.52 92440.5 1.43 93 390.1 3.09 94 390.1 3.57 95 532.1 1.52 H NMR (400 MHz,CD3CN) 7.94 (d, J = 8.4 Hz, 1H), 7.77 (s, 1H), 7.65 (d, J = 2.3 Hz, 1H),7.62-7.55 (m, 2H), 7.36- 7.32 (m, 2H), 7.22 (d, J = 8.2 Hz, 1H), 6.42(d, J = 9.4 Hz, 1H), 4.29 (t, J = 6.7 Hz, 2H), 3.49 (t, J = 6.7 Hz, 2H),2.90 (s, 3H), 2.32 (s, 3H), 1.62-1.58 (m, 2H), 1.19-1.15 (m, 2H) 96451.1 1.6 H NMR (400 MHz, CDCl3) 8.17 (s, 1H), 8.07-8.03 (m, 2H), 7.82(s, 1H), 7.26 (dd, J = 1.7, 8.2 Hz, 1H), 7.19- 7.16 (m, 2H), 6.69 (d, J= 10.4 Hz, 1H), 2.58 (s, 3H), 1.80-1.75 (m, 2 H), 1.27-1.22 (m, 2H). 97465.1 2 98 388.2 1.44 99 388.2 1.32 1H NMR, DMSO-d6: 1.11 (ABq, 2H, J =3.0, 6.0 Hz), 1.46 (ABq, 2H, J = 3.0, 6.0 Hz), 2.26 (s, 3H), 3.18 (t,2H, J = 6.0 Hz), 4.55 (t, 2H, J = 6.0 Hz), 6.35 (d, 1H, J = 9.0 Hz),6.89 (d, 1H, J = 3.0 Hz), 6.96 (dd, 1H, J = 3.0, 6.0 Hz), 7.26 (d, 1H, J= 6.0 Hz), 7.50 (d, 1H, J = 3.0 Hz), 7.59 (dd, 1H, 3.0, 6.0 Hz), 7.66(d, 1H, J = 6.0 Hz), 7.89 (d, 1H, J = 6.0 Hz), 8.27 (s, 1H), 11.76 (s,1H). 100 416.5 1.68 1H NMR (400.0 MHz, DMSO-d6) d 8.22 (dd, J = 1.9, 5.0Hz, 1H), 8.01 (s, 1H), 7.92 (s, 1H), 7.52 (dd, J = 1.9, 7.2 Hz, 1H),7.35 (s, 1H), 7.22 (d, J = 8.2 Hz, 1H), 7.07-7.03 (m, 1H), 6.77 (d, J =8.2 Hz, 1H), 4.50 (t, J = 8.8 Hz, 2H), 3.80 (s, 3H), 3.15 (t, J = 8.7Hz, 2H), 2.30 (s, 3H), 1.90 (s, 3H), 1.48-1.40 (m, 2H) and 1.10-1.05 (m,2H) ppm 101 416.5 1.66 1H NMR (400.0 MHz, DMSO-d6) d 8.16 (d, J = 2.4Hz, 1H), 8.03 (s, 1H), 7.91 (s, 1H), 7.71 (dd, J = 2.5, 8.5 Hz, 1H),7.36 (s, 1H), 7.23 (d, J = 8.2 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 6.79(d, J = 8.2 Hz, 1H), 4.55 (t, J = 8.8 Hz, 2H), 3.90 (s, 3H), 3.15 (t, J= 8.7 Hz, 2H), 2.30 (s, 3H), 2.10 (s, 3H), 1.48-1.45 (m, 2H) and1.10-1.08 (m, 2H) ppm 102 416.7 1.74 1H NMR (400.0 MHz, DMSO-d6) d 8.20(d, J = 5.2 Hz, 1H), 8.07 (s, 1H), 7.95 (s, 1H), 7.36 (s, 1H), 7.23 (d,J = 8.2 Hz, 1H), 6.94 (d, J = 5.2 Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H),6.74 (s, 1H), 4.53 (t, J = 8.8 Hz, 2H), 3.87 (s, 3H), 3.17 (t, J = 8.7Hz, 2H), 2.31 (s, 3H), 2.08 (s, 3H), 1.48- 1.46 (m, 2H) and 1.11-1.09(m, 2H) ppm 103 468.3 1.8 1H NMR (400.0 MHz, DMSO-d6) d 8.81 (s, 1H),7.85 (s, 1H), 7.54 (s, 1H), 7.42-7.31 (m, 3H), 6.67 (d, J = 8.4 Hz, 1H),3.86 (s, 3H), 2.30 (s, 3H), 2.08 (s, 3H), 1.92 (s, 3H), 1.51-1.48 (m,2H) and 1.17-1.15 (m, 2H) ppm 104 468.7 1.96 1H NMR (400.0 MHz, DMSO-d6)d 8.78 (s, 1H), 8.01 (s, 1H), 7.81 (s, 1H), 7.58-7.56 (m, 2H), 7.41-7.34(m, 2H), 3.91 (s, 3H), 2.30 (s, 3H), 2.17 (s, 3H), 2.13 (s, 3H), 1.50-1.48 (m, 2H) and 1.18-1.16 (m, 2H) ppm 105 454.5 1.81 1H NMR (400.0 MHz,DMSO-d6) d 8.98 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.5 Hz,1H), 7.55 (s, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H),6.88 (s, 1H), 6.64 (s, 1H), 3.85 (s, 3H), 2.42 (s, 3H), 2.21 (s, 3H),1.52-1.49 (m, 2H) and 1.18-1.16 (m, 2H) ppm 106 440.5 1.6 1H NMR (400.0MHz, DMSO-d6) d 11.66 (s, 1H), 8.96 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H),7.71 (d, J = 8.5 Hz, 1H), 7.56 (s, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.34(d, J = 8.3 Hz, 1H), 6.10 (s, 1H), 6.01 (s, 1H), 2.22 (s, 3H), 2.18 (s,3H), 1.52-1.49 (m, 2H) and 1.18-1.15 (m, 2H) ppm 107 440.5 1.72 1H NMR(400.0 MHz, DMSO-d6) d 11.78 (s, 1H), 8.84 (s, 1H), 7.97 (s, 1H), 7.91(s, 1H), 7.69 (s, 1H), 7.58 (s, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.38 (s,1H), 7.36 (d, J = 8.4 Hz, 1H), 2.32 (s, 3H), 2.02 (s, 3H), 1.53-1.50 (m,2H) and 1.20-1.18 (m, 2H) ppm 108 454.3 1.5 1H NMR (400.0 MHz, DMSO-d6)d 11.66 (s, 1H), 8.81 (s, 1H), 7.81 (s, 1H), 7.54 (s, 1H), 7.39 (d, J =8.3 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.19 (d, J = 9.3 Hz, 1H), 6.17(d, J = 9.3 Hz, 1H), 2.28 (s, 3H), 1.98 (s, 3H), 1.89 (s, 3H), 1.50-1.48(m, 2H) and 1.17-1.14 (m, 2H) ppm 109 402.5 1.41 1H NMR (400.0 MHz,DMSO-d6) d 11.66 (s, 1H), 8.06 (s, 1H), 7.93 (s, 1H), 7.39 (d, J = 6.6Hz, 1H), 7.36 (s, 1H), 7.23 (d, J = 8.2 Hz, 1H), 6.80 (d, J = 8.2 Hz,1H), 6.19 (s, 1H), 6.10 (d, J = 6.6 Hz, 1H), 4.55 (t, J = 8.8 Hz, 2H),3.19 (t, J = 8.7 Hz, 2H), 2.30 (s, 3H), 2.10 (s, 3H), 1.49- 1.46 (m, 2H)and 1.11-1.08 (m, 2H) ppm 110 523.5 1.86 1H NMR (400.0 MHz, DMSO-d6) d9.13 (s, 1H), 8.46 (s, 1H), 8.34 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.72(d, J = 8.5 Hz, 1H), 7.54 (s, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.32 (d, J= 8.3 Hz, 1H), 4.88 (s, 2H), 3.71 (s, 3H), 2.30 (s, 3H), 1.52-1.49 (m,2H) and 1.19-1.16 (m, 2H) ppm 111 454.5 1.58 1H NMR (400.0 MHz, DMSO-d6)d 11.60 (s, 1H), 8.82 (s, 1H), 7.75 (s, 1H), 7.55 (s, 1H), 7.42-7.29 (m,4H), 2.28 (s, 3H), 2.16 (s, 3H), 1.99 (s, 3H), 1.49-1.48 (m, 2H) and1.17-1.16 (m, 2H) ppm 112 402.3 1.33 1H NMR (400.0 MHz, DMSO-d6) d 11.72(s, 1H), 8.06 (s, 1H), 7.85 (s, 1H), 7.50 (d, J = 9.4 Hz, 1H), 7.41 (s,1H), 7.36 (s, 1H), 7.24 (d, J = 8.2 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H),6.35 (d, J = 9.4 Hz, 1H), 4.55 (t, J = 8.8 Hz, 2H), 3.21-3.17 (m, 2H),2.28 (s, 3H), 2.14 (s, 3H), 1.48-1.45 (m, 2H) and 1.10-1.08 (m, 2H) ppm113 440.5 1.6 114 402.5 1.18 1H NMR (400.0 MHz, DMSO-d6) d 11.78 (s,1H), 7.91 (s, 1H), 7.88 (s, 1H), 7.43 (d, J = 6.3 Hz, 1H), 7.36 (s, 1H),7.32 (d, J = 6.7 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 6.79 (d, J = 8.2 Hz,1H), 6.23 (t, J = 6.6 Hz, 1H), 4.54 (t, J = 8.7 Hz, 2H), 3.19 (t, J =8.7 Hz, 2H), 2.27 (s, 3H), 1.95 (s, 3H), 1.48-1.47 (m, 2H) and 1.09-1.08(m, 2H) ppm 115 386.5 1.58 1H NMR (400.0 MHz, DMSO-d6) d 11.76 (s, 1H),8.24 (s, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.58(d, J = 9.5 Hz, 1H), 7.50 (s, 1H), 7.36 (s, 1H), 7.27 (s, 2H), 6.35 (d,J = 9.5 Hz, 1H), 2.87 (t, J = 7.4 Hz, 4H), 2.26 (s, 3H), 2.03 (qn, J =7.4 Hz, 2H), 1.49-1.47 (m, 2H) and 1.13-1.12 (m, 2H) ppm 116 484.5 1.491H NMR (400.0 MHz, DMSO-d6) d 8.76 (s, 1H), 7.86 (d, J = 8.3 Hz, 1H),7.61 (d, J = 8.4 Hz, 1H), 7.56 (s, 1H), 7.49 (s, 1H), 7.40 (d, J = 8.3Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 7.26 (s, 1H), 4.88 (t, J = 5.3 Hz,1H), 3.95-3.92 (m, 2H), 3.62-3.58 (m, 2H), 2.06 (s, 3H), 2.04 (s, 3H),1.51- 1.48 (m, 2H), and 1.17-1.14 (m, 2H) ppm 117 440.5 1.58 1H NMR(400.0 MHz, DMSO-d6) d 11.68 (s, 1H), 8.75 (s, 1H), 7.74 (s, 1H), 7.58(s, 1H), 7.51 (d, J = 9.4 Hz, 1H), 7.43 (d, J = 8.3 Hz, 1H), 7.35 (d, J= 8.3 Hz, 1H), 7.04 (s, 1H), 6.20 (d, J = 9.5 Hz, 1H), 2.33 (s, 3H),2.24 (s, 3H), 1.52-1.50 (m, 2H) and 1.21-1.18 (m, 2H) ppm

Assays

Assays for Detecting and Measuring ΔF508-CFTR Correction Properties ofCompounds

Membrane potential optical methods for assaying ΔF508-CFTR modulationproperties of compounds

The optical membrane potential assay utilized voltage-sensitive FRETsensors described by Gonzalez and Tsien (See Gonzalez, J. E. and R. Y.Tsien (1995) “Voltage sensing by fluorescence resonance energy transferin single cells” Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y.Tsien (1997) “Improved indicators of cell membrane potential that usefluorescence resonance energy transfer” Chem Biol 4(4): 269-77) incombination with instrumentation for measuring fluorescence changes suchas the Voltage/Ion Probe Reader (VIPR) (See Gonzalez, J. E., K. Oades,et al. (1999) “Cell-based assays and instrumentation for screeningion-channel targets” Drug Discov Today 4(9): 431-439).

These voltage sensitive assays are based on the change in fluorescenceresonant energy transfer (FRET) between the membrane-soluble,voltage-sensitive dye, DiSBAC₂(3), and a fluorescent phospholipid,CC2-DMPE, which is attached to the outer leaflet of the plasma membraneand acts as a FRET donor. Changes in membrane potential (V_(m)) causethe negatively charged DiSBAC₂(3) to redistribute across the plasmamembrane and the amount of energy transfer from CC2-DMPE changesaccordingly. The changes in fluorescence emission were monitored usingVIPR™ II, which is an integrated liquid handler and fluorescent detectordesigned to conduct cell-based screens in 96- or 384-well microtiterplates.

1. Identification of Correction Compounds

To identify small molecules that correct the trafficking defectassociated with ΔF508-CFTR; a single-addition HTS assay format wasdeveloped. The cells were incubated in serum-free medium for 16 hrs at37° C. in the presence or absence (negative control) of test compound.As a positive control, cells plated in 384-well plates were incubatedfor 16 hrs at 27° C. to “temperature-correct” ΔF508-CFTR. The cells weresubsequently rinsed 3× with Krebs Ringers solution and loaded with thevoltage-sensitive dyes. To activate ΔF508-CFTR, 10 μM forskolin and theCFTR potentiator, genistein (20 μM), were added along with Cl⁻-freemedium to each well. The addition of Cl⁻-free medium promoted Cl⁻ effluxin response to ΔF508-CFTR activation and the resulting membranedepolarization was optically monitored using the FRET-basedvoltage-sensor dyes.

2. Identification of Potentiator Compounds

To identify potentiators of ΔF508-CFTR, a double-addition HTS assayformat was developed. During the first addition, a Cl⁻-free medium withor without test compound was added to each well. After 22 sec, a secondaddition of Cl⁻-free medium containing 2-10 μM forskolin was added toactivate ΔF508-CFTR. The extracellular Cl⁻ concentration following bothadditions was 28 mM, which promoted Cl⁻efflux in response to ΔF508-CFTRactivation and the resulting membrane depolarization was opticallymonitored using the FRET-based voltage-sensor dyes. SolutionsBathSolution #1: (in mM) NaCl 160, KCl 4.5, CaCl₂ 2, MgCl₂ 1, HEPES 10, pH7.4 with NaOH.

-   -   Chloride-free bath solution: Chloride salts in Bath Solution #1        are substituted with gluconate salts.    -   CC2-DMPE: Prepared as a 10 mM stock solution in DMSO and stored        at −20° C.    -   DiSBAC₂(3): Prepared as a 10 mM stock in DMSO and stored at −20°        C.

4. Cell Culture

NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR are used foroptical measurements of membrane potential. The cells are maintained at37° C. in 5% CO₂ and 90% humidity in Dulbecco's modified Eagle's mediumsupplemented with 2 mM glutamine, 10% fetal bovine serum, 1×NEAA, β-ME,1× pen/strep, and 25 mM HEPES in 175 cm² culture flasks. For all opticalassays, the cells were seeded at 30,000/well in 384-well matrigel-coatedplates and cultured for 2 hrs at 37° C. before culturing at 27° C. for24 hrs for the potentiator assay. For the correction assays, the cellsare cultured at 27° C. or 37° C. with and without compounds for 16-24hours Electrophysiological Assays for assaying ΔF508-CFTR modulationproperties of compounds

2. Using Chamber Assay

Using chamber experiments were performed on polarized epithelial cellsexpressing ΔF508-CFTR to further characterize the ΔF508-CFTR modulatorsidentified in the optical assays. FRT^(ΔF508-CFTR) epithelial cellsgrown on Costar Snapwell cell culture inserts were mounted in an Ussingchamber (Physiologic Instruments, Inc., San Diego, Calif.), and themonolayers were continuously short-circuited using a Voltage-clampSystem (Department of Bioengineering, University of Iowa, IA, and,Physiologic Instruments, Inc., San Diego, Calif.). Transepithelialresistance was measured by applying a 2-mV pulse. Under theseconditions, the FRT epithelia demonstrated resistances of 4 KΩ/cm² ormore. The solutions were maintained at 27° C. and bubbled with air. Theelectrode offset potential and fluid resistance were corrected using acell-free insert. Under these conditions, the current reflects the flowof Cl⁻through ΔF508-CFTR expressed in the apical membrane. The I_(SC)was digitally acquired using an MP100A-CE interface and AcqKnowledgesoftware (v3.2.6; BIOPAC Systems, Santa Barbara, Calif.).

2. Identification of Correction Compounds

Typical protocol utilized a basolateral to apical membraneCl⁻concentration gradient. To set up this gradient, normal ringer wasused on the basolateral membrane, whereas apical NaCl was replaced byequimolar sodium gluconate (titrated to pH 7.4 with NaOH) to give alarge Cl⁻concentration gradient across the epithelium. All experimentswere performed with intact monolayers. To fully activate ΔF508-CFTR,forskolin (10 μM) and the PDE inhibitor, IBMX (100 μM), were appliedfollowed by the addition of the CFTR potentiator, genistein (50 μM).

As observed in other cell types, incubation at low temperatures of FRTcells stably expressing ΔF508-CFTR increases the functional density ofCFTR in the plasma membrane. To determine the activity of correctioncompounds, the cells were incubated with 10 μM of the test compound for24 hours at 37° C. and were subsequently washed 3× prior to recording.The cAMP- and genistein-mediated I_(SC) in compound-treated cells wasnormalized to the 27° C. and 37° C. controls and expressed as percentageactivity. Preincubation of the cells with the correction compoundsignificantly increased the cAMP- and genistein-mediated I_(SC) comparedto the 37° C. controls.

3. Identification of Potentiator Compounds

Typical protocol utilized a basolateral to apical membraneCl⁻concentration gradient. To set up this gradient, normal ringers wasused on the basolateral membrane and was permeabilized with nystatin(360 μg/m), whereas apical NaCl was replaced by equimolar sodiumgluconate (titrated to pH 7.4 with NaOH) to give a largeCl⁻concentration gradient across the epithelium. All experiments wereperformed 30 min after nystatin permeabilization. Forskolin (10 μM) andall test compounds were added to both sides of the cell culture inserts.The efficacy of the putative ΔF508-CFTR potentiators was compared tothat of the known potentiator, genistein.

4. Solutions

Basolateral solution (in mM): NaCl (135), CaCl₂ (1.2), MgCl₂ (1.2),K₂HPO₄ (2.4), KHPO₄ (0.6),N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES) (10), anddextrose (10). The solution was titrated to pH 7.4 with NaOH.

Apical solution (in mM): Same as basolateral solution with NaCl replacedwith Na Gluconate (135).

5. Cell Culture

Fisher rat epithelial (FRT) cells expressing ΔF508-CFTR(FRT^(ΔF508-CFTR)) were used for Ussing chamber experiments for theputative ΔF508-CFTR modulators identified from our optical assays. Thecells were cultured on Costar Snapwell cell culture inserts and culturedfor five days at 37° C. and 5% CO₂ in Coon's modified Ham's F-12 mediumsupplemented with 5% fetal calf serum, 100 U/ml penicillin, and 100μg/ml streptomycin. Prior to use for characterizing the potentiatoractivity of compounds, the cells were incubated at 27° C. for 16-48 hrsto correct for the ΔF508-CFTR. To determine the activity of correctionscompounds, the cells were incubated at 27° C. or 37° C. with and withoutthe compounds for 24 hours.

6. Whole-Cell Recordings

The macroscopic ΔF508-CFTR current (I_(ΔF508)) in temperature- and testcompound-corrected NIH3T3 cells stably expressing ΔF508-CFTR weremonitored using the perforated-patch, whole-cell recording. Briefly,voltage-clamp recordings of I_(ΔF508) were performed at room temperatureusing an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc.,Foster City, Calif.). All recordings were acquired at a samplingfrequency of 10 kHz and low-pass filtered at 1 kHz. Pipettes had aresistance of 5-6 MΩ when filled with the intracellular solution. Underthese recording conditions, the calculated reversal potential forCl⁻(E_(Cl)) at room temperature was −28 mV. All recordings had a sealresistance >20 GΩ and a series resistance <15 MΩ. Pulse generation, dataacquisition, and analysis were performed using a PC equipped with aDigidata 1320 A/D interface in conjunction with Clampex 8 (AxonInstruments Inc.). The bath contained <250 μl of saline and wascontinuously perifused at a rate of 2 ml/min using a gravity-drivenperfusion system.

7. Identification of Correction Compounds

To determine the activity of correction compounds for increasing thedensity of functional ΔF508-CFTR in the plasma membrane, we used theabove-described perforated-patch-recording techniques to measure thecurrent density following 24-hr treatment with the correction compounds.To fully activate ΔF508-CFTR, 10 μM forskolin and 20 μM genistein wereadded to the cells. Under our recording conditions, the current densityfollowing 24-hr incubation at 27° C. was higher than that observedfollowing 24-hr incubation at 37° C. These results are consistent withthe known effects of low-temperature incubation on the density ofΔF508-CFTR in the plasma membrane. To determine the effects ofcorrection compounds on CFTR current density, the cells were incubatedwith 10 μM of the test compound for 24 hours at 37° C. and the currentdensity was compared to the 27° C. and 37° C. controls (% activity).Prior to recording, the cells were washed 3× with extracellularrecording medium to remove any remaining test compound. Preincubationwith 10 μM of correction compounds significantly increased the cAMP- andgenistein-dependent current compared to the 37° C. controls.

8. Identification of Potentiator Compounds

The ability of ΔF508-CFTR potentiators to increase the macroscopicΔF508-CFTR Cl⁻current (I_(ΔF580)) in NIH3T3 cells stably expressingΔF508-CFTR was also investigated using perforated-patch-recordingtechniques. The potentiators identified from the optical assays evoked adose-dependent increase in I_(ΔF508) with similar potency and efficacyobserved in the optical assays. In all cells examined, the reversalpotential before and during potentiator application was around −30 mV,which is the calculated E_(Cl) (−28 mV).

9. Solutions

Intracellular solution (in mM): Cs-aspartate (90), CsCl (50), MgCl₂ (1),HEPES (10), and 240 μg/ml amphotericin-B (pH adjusted to 7.35 withCsOH).

Extracellular solution (in mM): N-methyl-D-glucamine (NMDG)-Cl (150),MgCl₂ (2), CaCl₂ (2), HEPES (10) (pH adjusted to 7.35 with HCl).

10. Cell Culture

NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR are used forwhole-cell recordings. The cells are maintained at 37° C. in 5% CO₂ and90% humidity in Dulbecco's modified Eagle's medium supplemented with 2mM glutamine, 10% fetal bovine serum, 1× NEAA, β-ME, 1× pen/strep, and25 mM HEPES in 175 cm² culture flasks. For whole-cell recordings,2,500-5,000 cells were seeded on poly-L-lysine-coated glass coverslipsand cultured for 24-48 hrs at 27° C. before use to test the activity ofpotentiators; and incubated with or without the correction compound at37° C. for measuring the activity of correctors.

11. Single-Channel Recordings

The single-channel actdivities of temperature-corrected ΔF508-CFTRstably expressed in NIH3T3 cells and activities of potentiator compoundswere observed using excised inside-out membrane patch. Briefly,voltage-clamp recordings of single-channel activity were performed atroom temperature with an Axopatch 200B patch-clamp amplifier (AxonInstruments Inc.). All recordings were acquired at a sampling frequencyof 10 kHz and low-pass filtered at 400 Hz. Patch pipettes werefabricated from Corning Kovar Sealing #7052 glass (World PrecisionInstruments, Inc., Sarasota, Fla.) and had a resistance of 5-8 MΩ whenfilled with the extracellular solution. The ΔF508-CFTR was activatedafter excision, by adding 1 mM Mg-ATP, and 75 nM of the cAMP-dependentprotein kinase, catalytic subunit (PKA; Promega Corp. Madison, Wis.).After channel activity stabilized, the patch was perifused using agravity-driven microperfusion system. The inflow was placed adjacent tothe patch, resulting in complete solution exchange within 1-2 sec. Tomaintain ΔF508-CFTR activity during the rapid perifusion, thenonspecific phosphatase inhibitor F⁻ (10 mM NaF) was added to the bathsolution. Under these recording conditions, channel activity remainedconstant throughout the duration of the patch recording (up to 60 min)Currents produced by positive charge moving from the intra- toextracellular solutions (anions moving in the opposite direction) areshown as positive currents. The pipette potential (V_(p)) was maintainedat 80 mV.

Channel activity was analyzed from membrane patches containing ≦2 activechannels. The maximum number of simultaneous openings determined thenumber of active channels during the course of an experiment. Todetermine the single-channel current amplitude, the data recorded from120 sec of ΔF508-CFTR activity was filtered “off-line” at 100 Hz andthen used to construct all-point amplitude histograms that were fittedwith multigaussian functions using Bio-Patch Analysis software(Bio-Logic Comp. France). The total microscopic current and openprobability (P_(o)) were determined from 120 sec of channel activity.The P_(o) was determined using the Bio-Patch software or from therelationship P_(o)=I/i(N), where I=mean current, i=single-channelcurrent amplitude, and N=number of active channels in patch.

12. Solutions

Extracellular solution (in mM): NMDG (150), aspartic acid (150), CaCl₂(5), MgCl₂ (2), and HEPES (10) (pH adjusted to 7.35 with Tris base).

Intracellular solution (in mM): NMDG-Cl (150), MgCl₂ (2), EGTA (5), TES(10), and Tris base (14) (pH adjusted to 7.35 with HCl).

13. Cell Culture

NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR are used forexcised-membrane patch-clamp recordings. The cells are maintained at 37°C. in 5% CO₂ and 90% humidity in Dulbecco's modified Eagle's mediumsupplemented with 2 mM glutamine, 10% fetal bovine serum, 1×NEAA, β-ME,1× pen/strep, and 25 mM HEPES in 175 cm² culture flasks. For singlechannel recordings, 2,500-5,000 cells were seeded onpoly-L-lysine-coated glass coverslips and cultured for 24-48 hrs at 27°C. before use.

The exemplified compounds of Table 3 have an activity as shown below inTable 3.

TABLE 3 EC50: +++ <= 2.0 μM < ++ <= 5.0 μM <+ Percent Efficacy: + <=50.0% < ++ <= 100.0% < +++ Cmpd # EC50 % Efficacy 1 +++ ++ 2 +++ ++ 3+++ +++ 4 +++ ++ 5 +++ ++ 6 +++ +++ 7 +++ ++ 8 +++ ++ 9 +++ +++ 10 +++++ 11 +++ +++ 12 +++ ++ 13 + ++ 14 +++ ++ 15 +++ +++ 16 +++ ++ 17 ++++++ 18 +++ +++ 19 +++ +++ 20 +++ +++ 21 +++ ++ 22 +++ ++ 23 ++ ++ 24 ++++++ 25 +++ +++ 26 +++ ++ 27 +++ +++ 28 +++ ++ 29 +++ +++ 30 +++ ++ 31+++ ++ 32 ++ ++ 33 +++ +++ 34 ++ ++ 35 +++ ++ 36 +++ +++ 37 +++ +++ 38+++ +++ 39 +++ ++ 40 +++ +++ 41 +++ +++ 42 +++ ++ 43 +++ +++ 44 +++ ++45 +++ +++ 46 +++ ++ 47 +++ + 48 +++ +++ 49 +++ ++ 50 +++ ++ 51 +++ +++52 +++ ++ 53 +++ +++ 54 +++ ++ 55 +++ ++ 56 +++ +++ 57 +++ +++ 58 ++++++ 59 ++ ++ 60 +++ ++ 61 +++ ++ 62 +++ ++ 63 +++ ++ 64 +++ +++ 65 +++++ 66 +++ +++ 67 +++ +++ 68 +++ ++ 69 +++ ++ 70 +++ ++ 71 +++ +++ 72 ++++++ 73 +++ ++ 74 ++ + 75 +++ +++ 76 +++ ++ 77 +++ +++ 78 +++ ++ 79 ++++++ 80 +++ ++ 81 +++ +++ 82 +++ +++ 83 +++ ++ 84 +++ ++ 85 +++ +++ 86+++ +++ 87 +++ +++ 88 +++ +++ 89 +++ +++ 90 +++ +++ 91 +++ +++ 92 +++ ++93 +++ +++ 94 ++ +++ 95 +++ +++ 96 +++ +++ 97 +++ ++ 98 +++ ++ 99 ++++++ 100 +++ +++ 101 +++ +++ 102 +++ ++ 103 +++ +++ 104 +++ ++ 105 +++ ++106 +++ +++ 107 +++ +++ 108 +++ +++ 109 +++ ++ 110 +++ ++ 111 +++ +++112 +++ ++ 113 +++ +++ 114 +++ ++ 115 +++ ++ 116 +++ +++ 117 +++ +++

OTHER EMBODIMENTS

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

1-79. (canceled)
 80. A compound selected from the following table:

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50 51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92 93 94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117


81. A pharmaceutical composition comprising: (i) a compound according to claim 80; and (ii) a pharmaceutically acceptable carrier.
 82. The composition according to claim 81, further comprising a mucolytic agent, a bronchodialator, an antibiotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator, or a nutritional agent.
 83. A method of modulating CFTR activity comprising the step of contacting said CFTR with a compound according to claim
 80. 84. A method of treating or lessening the severity of a disease in a patient, wherein said disease is selected from cystic fibrosis, hereditary emphysema, COPD, or dry-eye disease, said method comprising the step of administering to said patient an effective amount of a compound according to claim
 80. 85. A kit for use in measuring the activity of CFTR or a fragment thereof in a biological sample in vitro or in vivo, comprising: (i) a composition comprising a compound according claim 80; and (ii) instructions for: a) contacting the composition with the biological sample; and b) measuring activity of said CFTR or a fragment thereof.
 86. The kit according to claim 85, further comprising instructions for a) contacting an additional composition with the biological sample; b) measuring the activity of said CFTR or a fragment thereof in the presence of said additional compound, and c) comparing the activity of said CFTR in the presence of the additional compound with the activity of said CFTR in the presence of a compound according to claim
 80. 